In September 1999, Keibler entered a nationwide contest held by World Championship Wrestling to find a new member of the Nitro Girls dance troupe. The results were decided by a series of polls on WCW's website, which narrowed down the field to eight finalists. Keibler was declared the winner of the contest on the November 8, 1999 edition of Nitro after receiving the most online votes out of the eight finalists and was given a spot on the dance troupe. Keibler performed dance routines every week on WCW's flagship show Monday Nitro under the name Skye.
She soon accepted a larger role and became a valet using the stage name Miss Hancock, briefly serving as an associate for the tag team of Lenny Lane and Lodi, dubbed Standards and Practices. Despite wearing business suits, her character was known to climb on top of the announcers' table and dance sensually.
During 2000, she dated David Flair, who was already involved in an on-screen relationship with Daffney. This led to Keibler's in-ring debut at the Bash at the Beach in a Wedding Gown match, which she lost after she removed her own gown. Hancock next briefly feuded with Kimberly Page, but the storyline ended abruptly when Page quit the company. Keibler and Flair then began a feud with the Misfits in Action stable, including a mud wrestling singles match against Major Gunns at New Blood Rising. During the match, she was kicked in the stomach, and she revealed herself to be pregnant the next night, beginning a new angle for herself and Flair. The angle, however, ended prematurely, as she revealed the pregnancy to be false, broke up with David Flair, and was taken off of television.
When she returned, she was known by her real name, Stacy Keibler, on-screen. On the March 12, 2001 edition of Nitro, Keibler revealed Shawn Stasiak as her "baby." She helped Stasiak defeat Bam Bam Bigelow in the final edition of Nitro two weeks later on March 26.
When WCW was purchased by the World Wrestling Federation (WWF) in 2001, Keibler's contract was bought by the WWF. Stacy made her WWF television debut on the June 14, 2001 episode of SmackDown! when then-face, Shane McMahon brought her to the ring to distract then-heel, Rhyno, causing him to lose a match. After this she portrayed a heel character in The Alliance; making great use of her good looks and long legs to help her achieve her wicked goals through any means necessary. She also showed that she had a sadistic side, as she loved watching other people’s pain and misfortune, and regularly enjoyed mocking them by pointing and laughing. She originally teamed up with then-heel Torrie Wilson, and the pair feuded with Trish Stratus and Lita. During this feud, the four wrestlers competed in the first-ever tag team bra and panties match at the Invasion pay-per-view, which Trish and Lita won by stripping Stacy and Wilson down to their bra and panties.
Towards the end of the WCW/ECW Invasion, Keibler managed the heel gimmicks of The Dudley Boyz and was nicknamed the "Duchess of Dudleyville". During this time, she began an on-screen rivalry with former ally Torrie Wilson after Wilson left The Alliance, with Keibler ordering The Dudley Boyz to put Torrie through a table, and taking great pleasure in her evil actions. Torrie, however, got her revenge after giving Keibler a wedgie then pantsing her on an episode of SmackDown!. She then defeated Keibler in the first-ever lingerie match, a match wrestled in lingerie, at No Mercy. Keibler made her WrestleMania debut at WrestleMania X8 alongside The Dudleyz. Keibler's role with the Dudley Boyz came to an abrupt end when she was powerbombed through a table after accidentally costing the team a match. She then set her sights on the WWE Women's Championship at Judgment Day, facing Trish Stratus in a losing effort. She faced Stratus several more times in the succeeding weeks, but she never won a match against her.
Keibler was originally drafted to the SmackDown! brand in 2002, where her character showed an interest in becoming the personal assistant to WWE chairman, then-heel, Vince McMahon. McMahon was ready to hire another attractive female until Keibler interrupted and performed a table dance in the ring. Keibler became McMahon's personal assistant, as well as his on-screen mistress. She was frequently shown flirting and 'making out' with him in backstage segments, until Stephanie McMahon became general manager of the SmackDown! brand. Then-babyface, Dawn Marie made her debut on SmackDown! as McMahon's legal assistant, who competed with Keibler for McMahon's affections.
A key storyline for Keibler's on-screen character occurred when she left SmackDown! for Raw. Keibler made her official Raw debut on August 12, 2002. For the remainder of 2002 and most of 2003, Keibler was paired with Test. As Test's on-screen marketing agent, she came up with the idea that Test should call his fans "Testicles," cut his hair, and reshape his image. The couple were originally villains, but due to popularity of the gimmick, they became fan favorites. In the spring of 2003, Test, however, became to verbally abuse Keibler, who also started managing Scott Steiner. After months of build-up, Keibler finally left Test for Steiner on the June 2 edition of Raw. Steiner defeated Test for Keibler's services at Bad Blood, and Keibler seemed happy as Steiner's new manager, as the two alluded to having more than a professional relationship. Test, however, continued to harass Keibler and Steiner until Steiner accepted a rematch with Stacy's services on the line. On the August 18 episode of Raw, Test won the match after faking a leg injury and then blindsiding Steiner with a big boot. A match was then set for Unforgiven with the stipulation that if Test won, he would not only retain Keibler's services, but would acquire Steiner's services as well. During the match, Keibler's interference backfired, and Test won the match. Steiner then turned heel by attacking Keibler after her interference in his match on the September 29 episode of Raw backfired. For a time, Test and Steiner worked as a tag team, sharing the services of Keibler as their on-screen sex slave. The storyline finally ended on the December 1 episode of Raw, when general manager Mick Foley freed Keibler from her obligatory contracts with Test and Steiner by temporarily firing them.
She was then placed in a feud involving Torrie Wilson and then-babyface, Sable, both of whom had recently posed for a Playboy cover. Keibler aligned with Miss Jackie, neither of whom had posed for the magazine, claiming that they deserved to be in Playboy over Sable and Wilson. Keibler and Jackie challenged Sable and Wilson to a tag team evening gown match at WrestleMania XX, which they lost when Jackie was pinned by Wilson, and the feud was dropped afterward.
She took over the 2004 Raw Diva Search for a few weeks, which led to several tag matches against the heel gimmicks of Gail Kim, Trish Stratus, and Molly Holly and with partners Nidia and Victoria. Keibler got upset victories over Kim, Stratus, and Holly. She earned a Women's Championship title match on October 11, 2004, but she was defeated by Stratus, who retained the title. Keibler also competed in the first-ever Fulfill your Fantasy Diva Battle Royal for the WWE Women's Championship at Taboo Tuesday along with Victoria, Nidia, Gail Kim, Molly Holly, Jazz, and then-champion Stratus. She was eliminated second to last after jumping over the top rope to avoid hitting the turnbuckle, followed by Holly knocking her off the apron to eliminate her.
In February 2005, Keibler began appearing in backstage segments with then-babyface, Randy Orton, and eventually became his on-screen girlfriend. When Orton challenged The Undertaker to a match at WrestleMania 21, Orton ended the relationship by hitting Stacy with an RKO, incapacitating her. He justified it by claiming he was demonstrating how ruthless he could be in order to defeat The Undertaker.
Keibler then joined forces with The Hurricane and Rosey. She became one-third of the trio as a superhero sidekick nicknamed Super Stacy, complete with her own superhero costume. She was ringside during several matches as they defended their World Tag Team Championship. During this time, Keibler feuded on-screen with then-heel, Victoria, including confrontations and a mixed-tag-team match on Raw and a singles match on Heat.
After a long tenure on Monday nights, Keibler and Christy Hemme were moved to SmackDown! on August 25, as part of a trade that brought Torrie Wilson and Candice Michelle to Raw. On SmackDown!, Keibler participated in lingerie matches and bikini contests. After a short absence, Keibler began a short feud with Jillian Hall, which led to the two having a match on Velocity, which Keibler lost. This would be Keibler's final match with WWE. Keibler's final mention on WWE programming occurred on the March 6, 2006 episode of Raw, where she was insulted by Candice Michelle during Michelle's unveiling of her Playboy magazine cover. Keibler officially parted ways with WWE in July 2006.
On April 6, 2019, Keibler made a surprise return to induct Torrie Wilson into the WWE Hall of Fame. On March 27, 2023, Keibler herself was announced as an inductee into the WWE Hall of Fame.