[5] While doing summer stock theater in Alabama, Jackson met former child actor Johnny Crawford of the 1950s television series The Rifleman, who cast her in his nightclub act.

[12] Following a role in the short-lived 1985 television series Half Nelson,[13] Jackson received an offer to audition for the cast of Saturday Night Live.

Because she was not confident her audition had gone well, she performed several impersonations on her next Tonight Show appearance and sent the tape to SNL's Lorne Michaels.

[14][15] A regular cast member from 1986 to 1992,[16] Jackson often appeared on the show's weekly Weekend Update segment as a correspondent who goes off topic, reciting poetry and doing backbends or handstands on the desk.

[5][17] During her tenure on SNL, Jackson was cast in a number of films, including Baby Boom, Family Business, I Love You to Death,[16] UHF,[7] The Pick-up Artist,[18] The Couch Trip,[19] and Casual Sex?.

[21] Jackson had a regular role as Patty in the 2000–2001 Comedy Central sitcom Strip Mall and in the 2003–2004 seasons of the Nickelodeon show Romeo!.

[25] In October 2008, she appeared with other celebrities on The O'Reilly Factor in a National Republican Senatorial Committee advertisement poking fun at Al Franken, a fellow Saturday Night Live alumnus then running for the United States Senate from Minnesota.

When accused of homophobia, Jackson countered that the label was merely a "cute liberal buzzword" and suggested that Glee be replaced with a show promoting celibacy.

[34] In 2011, Jackson joined the staff of Patriot Update as a writer and video blogger and host of the talk show Politichicks.

[5] Shortly thereafter, she reconnected with her high school sweetheart, Paul Wessel, then a Miami-Dade SWAT team police officer, and they married and had a daughter.

[45] She announced through an Instagram post in August 2024 that her breast cancer had metastasized and she had been diagnosed with an inoperable tumor in her windpipe.