On the March 19, 2019 episode of SmackDown Live, Dominik Mysterio appeared with his father, Rey Mysterio, who announced that he would be facing Samoa Joe for the WWE United States Championship at WrestleMania 35. He once again appeared on Raw from April to June, during the feud between Mysterio and Joe. During the following months, he was involved in his father's storylines and matches, including getting physically involved in Rey's WWE Championship match against Brock Lesnar at Survivor Series, where they attacked Lesnar and performed a double 619, but Rey was nonetheless defeated.
In May 2020, Dominik again assisted his father, this time in dealing with Seth Rollins and his teammates Murphy and Austin Theory, after his father suffered a severe eye injury. At The Horror Show at Extreme Rules, Rey had his eye removed in an Eye for an Eye match, where the winner could only be declared upon removing an opponent's eyeball from its socket. Dominik thereafter unsuccessfully came for revenge, having to be saved by his father's ally, Aleister Black. On the August 3 episode of Raw, Dominik issued a challenge to Rollins, which he accepted for SummerSlam, in what was Dominik's in-ring debut. The following week, after the SummerSlam match was made official, Rollins and Murphy attacked Dominik, landing over thirty kendo stick shots.
On August 23 at SummerSlam, Dominik made his in-ring debut, where he was defeated by Rollins in a street fight. The following night on Raw, Dominik and Rey teamed together for the first time in an official match, where they faced Rollins and Murphy, but the match ended in a disqualification after Retribution attacked the Mysterios. Six days later at Payback, The Mysterios defeated Rollins and Murphy to earn Dominik's first official victory in WWE. The next night on Raw, Dominik replaced his injured father in a match with Rollins, set up to determine entries into another match that was held later that night to decide the next challenger for the WWE Championship. Rollins avoided a frog splash, and went on to defeat Dominik, as a frustrated Rey looked on backstage. Next week, he defeated Murphy with the help of his family in a street fight. The following week on Raw, Dominik once again wrestled Rollins, this time in a steel cage match where he was defeated. A new storyline developed in September, where Dominik's sister Aalyah began to show feelings for Murphy, the former disciple of Rollins. This caused unrest amongst the Mysterio family, and one such distraction caused Murphy to pin Dominik during a match. As part of the 2020 Draft in October, The Mysterios were drafted to the SmackDown brand. The Mysterio family's feud with Rollins would end on the November 13 episode of SmackDown after Rey defeated Rollins in a No Holds Barred match after assistance from Murphy, who turned on Rollins.
At the 2021 Royal Rumble, Dominik took part in his first Royal Rumble match where he eliminated King Corbin before being eliminated by Bobby Lashley. On the February 12 episode of SmackDown, the Mysterios were defeated by Corbin and Sami Zayn in an Elimination Chamber qualifying match. On the WrestleMania edition of SmackDown, the Mysterios would face defending champions Dolph Ziggler and Robert Roode, Alpha Academy (Chad Gable and Otis), and The Street Profits in a fatal four-way tag team match for the SmackDown Tag Team Championship, but were unsuccessful as Ziggler and Roode retained their titles.
At WrestleMania Backlash, despite Dominik being attacked backstage by Ziggler and Roode prior to the match, Dominik and Rey won the SmackDown Tag Team Championship, marking Dominik's first championship in WWE, and making Dominik and Rey the first father and son team to become tag team champions in WWE history. On the June 4 episode of SmackDown, the Mysterios successfully defended their titles against The Usos, albeit with controversy as Jimmy Uso's shoulder was lifted although the referee wasn't aware. After Adam Pearce and Sonya Deville granted a rematch later that same night, the Mysterios again retained their titles after Roman Reigns interfered and attacked the Mysterios, causing a disqualification, and both were assaulted by Reigns afterwards. The following week on SmackDown, Rey called out Reigns for attacking Dominik, and challenged Reigns to a Hell in a Cell match at the namesake pay-per-view, but before Reigns could answer, Rey attacked Reigns with a kendo stick, but was ultimately overpowered, and while Dominik joined the brawl, Reigns powerbombed Dominik over the top rope and out of the ring. The next day on Talking Smack, Paul Heyman, Reigns' "special council", formally accepted Rey's challenge on Reigns's behalf. On June 17, however, the match was moved to the SmackDown prior to the pay-per-view in which Rey lost to Reigns. On the Money in the Bank pre-show, The Mysterios dropped the titles to The Usos, ending their reign at 63 days.
As part of the 2021 Draft, both Rey and Dominik were drafted to the Raw brand. On the January 31, 2022 episode of Raw, The Miz defeated Dominik. The following week, the Mysterios were guests on Miz TV. Rey claimed that Miz cheated to defeat Dominik while Miz took issue that Rey had an opportunity to qualify for the WWE Championship Elimination Chamber match while he did not, and also that Rey was the cover star of the WWE 2K22 video game. Dominik then defeated Miz in a rematch. Rey then defeated Miz during the Elimination Chamber Kickoff pre-show. Later backstage, Miz accused Rey of cheating due to Dominik and said he would find a tag team partner who was a "global superstar". On the following episode of Raw, as Miz teased the identity of his partner to face Rey and Dominik at WrestleMania 38, the Mysterios interrupted, stating it did not matter who Miz had chosen. Miz then revealed his partner to be Logan Paul, after which, Miz and Paul attacked the Mysterios. At WrestleMania 38, the Mysterios were defeated by Miz and Paul.
The Mysterios later began feuding with The Judgment Day (Finn Bálor, Damian Priest, and Rhea Ripley) over the group's desire to recruit Dominik, with the latter continuously refusing, leading to the group attacking the Mysterios in several occasions. During Rey's 20th Anniversary celebration on the July 25 episode of Raw, the Mysterios defeated Bálor and Priest in a tag team match. Afterwards in a backstage segment, Ripley attacked Rey's daughter Aalyah before dragging Dominik away, leading Rey into an assault by Bálor and Priest. At SummerSlam, the Mysterios defeated Bálor and Priest in a no disqualification match following an interference from the returning Edge, the Judgment Day's former leader, who attacked Bálor and Priest, allowing the Mysterios to defeat them. At Clash at the Castle, after Rey and Edge defeated Bálor and Priest, Dominik hit Edge with a low blow. Rey pleaded with Dominik to stop, but Dominik hit a devastating clothesline on Rey, turning heel and disbanding the Mysterios in the process.