For her portrayal of Jill Kendall on the CBS sitcom Mom (2014–2021), she was nominated for the Critics' Choice Television Award for Best Supporting Actress in a Comedy Series.

Pressly headlined the independent film Poor White Trash (2000), playing scheming gold-digger Sandy Lake, and appeared in three 2001 theatrical releases aimed at a teenage audience, which despite varying degrees of success, helped her receive more exposure.

In a profile, The New Yorker, describing this phase of her career, asserted: "She is typically cast on the strength of her looks and her Southern sassiness, and she has had girlfriend roles in several forgettable teensploitation flicks".

[8] Between 2005 and 2009, Pressly played Joy Turner, the pessimistic, cold-hearted, stubborn and vain ex-wife of a small-time thief, in the NBC sitcom My Name Is Earl, which was a success with critics and audiences.

[10] Pressly once called her role her "greatest release" and thanked creator Greg Garcia for restoring her faith in the business.

To those of you My Name is Earl fans who are just now discovering the juicy talents of the perpetually sneering, eye-rolling, attitude machine known as Jaime Pressly, I'd recommend you check out her work in flicks like Ringmaster, Tomcats, Joe Dirt, Torque, and Not Another Teen Movie.

Basically, if we were giving out an award for "the consistently best thing in a series of generally atrocious comedies," Jaime would be walking home with that prize, no sweat.

[13] In 2006, she also hosted the first annual VH1 Rock Honors,[14] and an episode of Saturday Night Live, and guest-starred on MADtv, playing Hillary Clinton in a parody of My Name Is Earl, "My Name Is Dubya", in which George W. Bush (Frank Caliendo) makes a list of all the bad things he has done in the past and rectifies them one by one.

[16] In I Love You, Man (2009), Pressly starred opposite Paul Rudd and Jason Segel, as the best friend of a bride-to-be and one half of a volatile married couple.

[20] The ABC Family television film Beauty & the Briefcase (2010), co-starring Hilary Duff, featured Pressly as a primary editor at Cosmopolitan magazine.

[21] Smoke Screen, another 2010 television film, saw her star as a reporter finding herself in the middle of a murder investigation when she wakes up next to a dead body.

In 2010, Pressly also guest-starred in two episodes of the CBS comedy Rules of Engagement, as a possible surrogate mother for Jeff and Audrey (Patrick Warburton and Megyn Price).

[22] In 6 Month Rule (2011), an independent film released for limited theaters and digital markets,[23] Pressly played what was described as a "harridan of an ex-fiancée" by the New York Times.

[24] She appeared in the interactive educational children's musical comedy The Oogieloves in the Big Balloon Adventure (2012), as a flamenco dancer riding a giant flying sombrero.

[29] Finders Keepers, a television horror film, saw Pressly play a divorced mother whose life is thrown into turmoil when her young daughter becomes obsessed with an evil doll left behind by the previous owners.

[43][44] She has graced the covers of numerous magazines, including InStyle Weddings, Ocean Drive, Health, Esquire, Redbook, Shape, Stuff, Maxim and Playboy.

[53] On January 5, 2011, two weeks before filing for divorce, Pressly was arrested in Santa Monica, California, for suspicion of driving under the influence.