Michaels attended California State University, Northridge, supporting herself as a bartender and personal trainer during that time. After working briefly as an agent with International Creative Management, in 2002, Michaels opened the sports medicine facility Sky Sport & Spa in Beverly Hills.

Michaels was an original trainer on the reality series The Biggest Loser when the show debuted in October 2004. On the show, she assumed the role of Red Team trainer and remained in that capacity for the first two seasons. After her departure in 2006, she was replaced by Kim Lyons. She returned to the show in 2007 as the Black Team trainer competing against Lyons’ Red Team and Bob Harper’s Blue Team. Along with Harper, Michaels was also a trainer in the Australian version of the show from 2006 to 2008.

Jillian launched her company Empowered Media LLC in 2008 and released her fitness video membership website called Fitfusion.com, often referred to as the Netflix of fitness, featuring top fitness and yoga trainers and celebrities including Dashama, Tara Stiles, Cassey Ho, Crunch Fitness, Jennifer Nicole Lee, Tone It Up, Zuzka Light, and others. Fitfusion is also associated and broadcasts on AT&T U-verse, BroadbandTV Corp, Bell Satellite TV Canada, and other TV channels, as well as Roku, Apple TV, and Fitness on Demand reaching audiences in Marriott, Hilton Worldwide and Shangri-La Hotels and Resorts.

On December 7, 2010, Michaels announced via Twitter that the eleventh season of the show would be her last. Michaels made her last appearance on The Biggest Loser on May 24, 2011.

On June 1, 2010, NBC debuted Losing It With Jillian, a spin-off of The Biggest Loser. In the show, Michaels visits the home and workplaces of family members for a week.

Since February 2011, Michaels has hosted a weekly podcast, The Jillian Michaels Show, through iTunes. In December 2011, the show was among the podcasts honored by Apple in its App Store Rewind 2011, winning in the Best New Audio Podcast category.

On May 6, 2011, CBS Television Distribution announced that Michaels had signed a multi-year deal to become a co-host of the panel-discussion show The Doctors, as well as to serve as a special correspondent on the CTD program Dr. Phil. Michaels had been a guest on The Doctors several times previously. On the show, Michaels hosted a recurring segment called Ask Jillian, which dealt primarily with nutrition and diet topics.

On September 4, 2012, it was announced that Michaels will return to The Biggest Loser in Season 14. Michaels also returned for Season 15, which premiered on October 15, 2013, on NBC, but did not return for Season 16 which aired in the fall of 2014.

Michaels left The Doctors in January 2012 after half a season, because, she claimed, the arrangement “wasn’t the fit both the show and I hoped for”.

Michaels has two children with her ex-fiancée Heidi Rhoades. Michaels adopted their then-two-year-old daughter(Lukensia Michaels Rhoades) from Haiti in May 2012, and Rhoades gave birth to a son(Phoenix Michaels Rhoades) that same month. On her sexuality, Michaels has stated, “Let’s just say I believe in healthy love. If I fall in love with a woman, that’s awesome. If I fall in love with a man, that’s awesome. As long as you fall in love…it’s like organic food. I only eat healthy food, and I only want healthy love!” The couple announced the end of their relationship in June 2018.

In September 2020, Michaels told Fox Business that she had recently recovered from COVID-19. She said that she was “able to get on the other side of it pretty quick.”