Marella made his World Wrestling Entertainment (WWE) debut on the April 16, 2007 episode of Raw from Milan, Italy. He was the opponent selected by Vince McMahon for Umaga as a fan. The unknown Marella scored a surprising upset, and won the WWE Intercontinental Championship with an assist from Bobby Lashley. The next day, WWE.com posted a profile on Marella, saying he was an Italian national who moved to Canada as a child and returned to his native country a few times each year to visit family. Shortly after winning the Intercontinental title, Marella feuded with Chris Masters, narrowly retaining the title in his first defenses. On July 2, he dropped the title to Umaga, after defeating him on June 24, at Vengeance: Night of Champions, by disqualification.
Marella then began a gradual heel turn and became increasingly jealous of his girlfriend, Maria. Over several weeks, they appeared together in a series of segments on Raw, including two "game show" skits, hosted by General Manager William Regal, which resulted in retired wrestler Ron Simmons winning a date with Maria, to Santino's dismay.
Marella began a publicity campaign against the WWE Films production, The Condemned, as its DVD release neared. He was eventually confronted by the film's star, Steve Austin, who argued the film's merits before delivering a Stone Cold Stunner to Marella and hosing him and Maria with beer. During the Austin angle, Marella repeatedly mocked him and his catchphrases in humorously broken English, starting a new comedic trend in his gimmick.
After a short angle with Jerry Lawler, which included Lawler hitting his signature fist drop maneuver after Marella lost a match to the returning Chris Jericho on the November 26 episode of Raw, Marella formed a tag team with Carlito.
Around this time, Maria was offered a photo shoot for Playboy magazine. After unsuccessfully persuading her to decline it, Marella tried to sabotage the cover unveiling (an in-ring segment of Raw), causing Maria to dump him. At WrestleMania XXIV, Maria had a "Playboy BunnyMania Lumberjack match". Santino interfered near the end of the match, pulling Maria off of a pin, and was punched by Jerry Lawler. After the match (which Maria's team lost), he was clotheslined by guest "Master of Ceremonies", Snoop Dogg. The next night on Raw, Maria wrestled Marella. Seven other women ganged up on him, and held his legs apart for Maria to headbutt his testicles and pin him. This ended their feud.
Marella and Carlito then feuded with Hardcore Holly and Cody Rhodes over the World Tag Team Championship. During a title match between them, Roddy Piper distracted Marella, who was then pinned. This sparked a rivalry with Piper.
On the July 14, 2008 episode of Raw, Marella lost to Beth Phoenix, who had answered his open challenge. On the next episode, after he lost another open challenge to the returning D'Lo Brown, Marella and Phoenix kissed, both looking confused afterward. Over the next few weeks, they became a parody of a "power couple", soon called "Glamarella" (a portmanteau of Phoenix's nickname, "Glamazon", and "Marella"). At SummerSlam, they wrestled Intercontinental Champion Kofi Kingston and WWE Women's Champion Mickie James in a mixed tag match with both titles on the line. Phoenix pinned James after hitting her finisher, the Glam Slam, giving Marella his second Intercontinental Championship.
Marella then sought to become the "greatest Intercontinental Champion of all the times" by beating The Honky Tonk Man's record 64-week reign. Over the weeks, a "Honk-A-Meter" graphic informed viewers of his progress during his matches and segments. At Cyber Sunday, Marella was disqualified in a title match with The Honky Tonk Man (who fans voted for over other former champions Roddy Piper and Goldust). On the November 10 episode of Raw, after a reign of twelve weeks and one day, Marella lost the title to William Regal.
In January 2009, Marella entered the Royal Rumble, at number 28. He was eliminated by Kane after (officially) 1.9 seconds, breaking The Warlord's 1989 record for shortest Royal Rumble appearance by a tenth of a second.
Marella's humor proved popular with audiences, and he turned face again before WrestleMania XXV, expressing his desire to be crowned the inaugural "Miss WrestleMania" in a 25-woman battle royal at the event. He challenged Mickie James to a match with one arm tied behind his back, with a battle royal spot on the line, but he lost. The next week, in order to "prove" his eligibility, he revealed he was wearing a mankini. Instead, he was attacked by most of the female roster. Nevertheless, at WrestleMania, he won the battle royal, competing in drag as Santina Marella (Santino Marella's self-alleged twin sister), last eliminating Beth Phoenix and Melina.
Marella successfully defended the Miss Wrestlemania title against Phoenix at Backlash in three seconds, with help from The Great Khali. On the May 18 Raw, Marella lost the title to Vickie Guerrero, and won it back on June 7, at Extreme Rules, by defeating Vickie and Chavo Guerrero in a handicap hog pen match. On the June 22 Raw, Raw's new owner, Donald Trump, fired Santina and the Miss WrestleMania title was abandoned.
At WrestleMania XXVI, Santino Marella competed in the 26-man battle royal dark match, won by Yoshi Tatsu. He then tried to form a tag team with Vladimir Kozlov, who repeatedly refused the offer. On the May 31 episode of Raw, Kozlov interfered in Marella's match, helping him win. On the July 19 Raw, they finally teamed to defeat William Regal and Zack Ryder. At Night of Champions, Marella and Kozlov wrestled a tag team turmoil match for the Unified Tag Team Championship, won by Cody Rhodes and Drew McIntyre.
On the October 11 Raw, he defeated Zack Ryder to qualify for Team Raw at Bragging Rights, against Team SmackDown. He was the first of seven Team Raw members eliminated, pinned by Tyler Reks. On the October 25 Raw, after Sheamus had called him an "embarrassment" for being the first man eliminated at Bragging Rights, Marella scored an upset victory over the former two-time WWE Champion. They wrestled twice more, with both matches ending with John Morrison saving Marella from Sheamus' post-match assault.
On the November 15 Raw, Marella and Kozlov became number one contenders for the WWE Tag Team Championship by defeating The Usos. They unsuccessfully challenged The Nexus (Justin Gabriel and Heath Slater) for the title at Survivor Series. They won the Tag Team Championships in a four-way elimination tag match on the December 6 Raw, beating The Nexus, The Usos and Mark Henry and Yoshi Tatsu, after John Cena distracted Gabriel, allowing Marella to hit his Cobra finisher. After celebrating in the ring, Tamina kissed Santino, starting a relationship between them. She began accompanying Marella to his matches. Marella and Kozlov retained the Tag Team Titles at TLC: Tables, Ladders & Chairs, when Gabriel and Slater were disqualified after interference from Nexus member Michael McGillicutty. The next night on Raw, Marella and Tamina beat Ted DiBiase and Maryse in a mixed tag match. On January 30, 2011, Marella entered the Royal Rumble at number 37. He was one of the final two wrestlers, before being eliminated by Alberto Del Rio. At Elimination Chamber, Marella and Kozlov lost the Tag Team Titles to Gabriel and Slater. At WrestleMania XXVII, Marella teamed with Big Show, Kane, and Kofi Kingston (replacing the injured Kozlov) to defeat The Corre (Slater, Gabriel, Ezekiel Jackson and Wade Barrett) in an eight-man tag match. Marella's relationship with Tamina ended when she was drafted to SmackDown. On August 5, Kozlov was released from WWE, ending the team.
Marella began teaming with Zack Ryder on the July 21 Superstars, beating WWE Tag Team Champions David Otunga and Michael McGillicutty in a non-title match. On the August 1 Raw, Otunga and McGillicutty won the rematch.
On September 1, Marella injured his left shoulder before a house show in Puerto Rico, rendering him inactive for several weeks. Marella returned on the October 3 Raw, defeating Jinder Mahal. On the October 31 episode, Marella defeated Jack Swagger with a roll-up pin after he spit water given to him by special guest, Beaker of The Muppets, in Swagger's face. The following Raw, Swagger defeated Marella by submission. On the January 6, 2012 episode of SmackDown, Marella defeated Drew McIntyre to become SmackDown General Manager Theodore Long's assistant. Marella teamed with Yoshi Tatsu on the January 27 SmackDown and "Hacksaw" Jim Duggan on the February 3 episode to face Tag Team Champions Primo & Epico, losing both times. On the February 17 SmackDown, Marella won a battle royal to replace Randy Orton in the Elimination Chamber match for the World Heavyweight Championship at Elimination Chamber. At the pay-per-view, he was the last man eliminated by Daniel Bryan.
On the March 5 Raw, Marella defeated Jack Swagger to win the United States Championship. On the following episode of SmackDown, Marella successfully defended the title against Swagger in a steel cage match, by escaping through the cage door. At WrestleMania XXVIII on April 1, Marella was the team captain of Team Teddy, which lost to Team Johnny, after interference from Eve. The following night on Raw, Marella successfully defended the title against Swagger and Dolph Ziggler in a triple threat match, and against David Otunga on the April 16 episode. On the pre-show of Extreme Rules on April 23, Marella defeated The Miz to retain the United States Championship. The following night on Raw, Marella unsuccessfully tried to earn a WWE Championship match at Over the Limit in a Beat the Clock Challenge against The Miz. Later that month, Marella briefly reunited with Zack Ryder, facing teams including Primo and Epico, Curt Hawkins and Tyler Reks and Titus O'Neil and Darren Young. Marella then feuded with Alberto Del Rio's ring announcer Ricardo Rodriguez, leading to a non-title Tuxedo match on June 17 at No Way Out, which Marella won. On the June 25 Raw, Marella successfully defended the United States Championship against Jack Swagger. Four days later on SmackDown, he and Intercontinental Champion Christian defeated David Otunga and Cody Rhodes to qualify for the World Heavyweight Championship Money in the Bank ladder match at Money in the Bank, which was won by Dolph Ziggler. On the July 27 and August 3 episodes of SmackDown, Marella lost to Antonio Cesaro in non-title matches. On August 19, on the SummerSlam pre-show, Marella lost the United States Championship to Cesaro. Marella lost his rematch for the title on the September 3 episode of Raw. On the September 21 episode of SmackDown, Marella defeated Cesaro in a non-title match to earn another shot at the United States Championship. The title rematch took place the following week on SmackDown, where Marella failed in his title challenge.
On the debut episode of WWE Main Event on October 3, Marella and Zack Ryder entered a Tag Team Championship tournament, and defeated Justin Gabriel and Tyson Kidd in the quarterfinals. The following week on Raw, they were eliminated in the semifinals by eventual winners Team Rhodes Scholars (Cody Rhodes and Damien Sandow). After this loss, Marella and Ryder began a feud with 3MB's members (Heath Slater, Drew McIntyre and Jinder Mahal) which culminated on the pre-show of Survivor Series, in which Slater and Mahal defeated them. On December 26, 2012, on Main Event, Marella participated in a 20-man battle royal for the number one contendership of Cesaro's United States Championship, and split from his partner Zack Ryder, when he eliminated him. Successively, Marella was eliminated by Wade Barrett from the battle royal. Marella then took a leave of absence due to a neck injury. Marella returned on January 27, 2013, at the Royal Rumble, entering the Royal Rumble at number five before being the first man eliminated by Cody Rhodes. After a two-month absence, Marella returned to Raw on April 1, losing to Mark Henry.
Marella returned on the September 9 episode of Raw, defeating Antonio Cesaro. On the next episode of SmackDown, he defeated Damien Sandow with the Cobra. On the September 23 episode of Raw, he suffered his first defeat against Fandango since his return from injury. He defeated Heath Slater on the next episode of SmackDown and began to align himself with The Great Khali and Hornswoggle. Marella then began a feud with Cesaro and his tag team partner, Jack Swagger. Santino defeated Swagger on the September 20 episode of SmackDown, and he defeated Cesaro on the September 30 episode of Raw in singles competition. On October 6 at Battleground, Marella and The Great Khali were defeated by Cesaro and Swagger in a tag team match. They were defeated again by The Real Americans on the following episode of Raw; after the match Marella attacked Cesaro with the Cobra. On the October 21 episode of Raw, he defeated Heath Slater, dressed as Elvis Presley. After the match, he danced on the announce table. After that, he took a brief hiatus once again.
On February 3, 2014, Marella returned to television and invited Emma into the ring from the crowd to have a "dance-off" with Summer Rae, starting a feud with her and Fandango. Emma would go on to win the dance competition against Summer Rae the February 21 episode of SmackDown. Santino participated in the André the Giant Memorial Battle Royal at WrestleMania XXX, eliminating The Miz, before being eliminated by Alberto Del Rio. On May 5, Santino participated in a 20-man battle royal for Dean Ambrose's United States Championship, but he was eliminated by RybAxel (Ryback and Curtis Axel).
After a third neck injury, Marella declared his retirement on July 6 at a house show in Toronto, Ontario.
Marella made several appearances throughout 2014 and 2015, including one appearance on the November 24 episode of Raw to promote his new movie, Jingle All the Way 2 with co-star Larry the Cable Guy, serving as the guest general manager for the December 5 episode of SmackDown, and hosted his own Royal Rumble lottery on January 20, exclusively on the WWE Network. Marella made his return to WWE television on the December 21 episode of Raw to present an award at the Slammy Awards. The next night, on Super SmackDown, Marella became angry when Stardust and The Ascension ruined his Christmas party and vowed revenge, receiving the help of Neville and Titus O'Neil. On May 6, 2016, after not appearing on WWE television in 2016, Marella was released from WWE along with seven other superstars.
On July 22, 2019, Marella appeared at the Raw Reunion show in a backstage skit. Marella would make a surprise appearance during the 2020 women's Royal Rumble match under his character of Santina Marella, where he entered at 29, becoming the first male to enter a women's Royal Rumble match, before shenanigans ensued when he eliminated himself via The Cobra after being startled and intimidated by Natalya and Beth Phoenix.