She is also well known for her critically acclaimed one-woman monologue, God Said, Ha! played on Broadway at the Lyceum theater in 1996. Miramax released the film version of the show in 1998 which was produced by Quentin Tarantino. The CD version of the show was nominated for a Grammy. More recently, she was consulting on the HBO show, Sex and the City, and has written and performed two other monologues, and appeared as a guest star in several TV shows.

The oldest in a family of five children raised in Spokane, Washington, Sweeney quickly found a talent for imitating voices and characters. Despite successful appearances in high school plays, she decided to put acting aside while she pursued her economic studies at the University of Washington.

After graduation, Sweeney headed south to Los Angeles to work as an accountant for Columbia Pictures. Once there, she decided on a whim to sign up for classes with the improvisational comedy troupe The Groundlings. It only took one class to convince her that acting was her true calling. Steadily auditioning, she continued to develop her characters with the troupe such as "Mea," the character that inspired the play Mea's Big Apology, which won the Best Written Play Award from L.A. Weekly in 1988 and has been developed by Sweeney into a screenplay, and "Pat," an androgynous person whose gender mystified others. At a Groundlings performance, she was discovered by Saturday Night Live producer Lorne Michaels and tapped for the late-night show, with which she stayed for four hit seasons.

Sweeney spun one of her most popular characters into the feature film It's Pat, and after leaving Saturday Night Live, moved back to Los Angeles. The film was a flop at the box office, but still has a cult following.

Within a matter of months, after moving back to L.A., Sweeney's brother was diagnosed with cancer, and so was she. Her experiences led her to write and star in God Said, Ha! Released theatrically by Miramax, the film version of the play earned the Golden Space Needle Award for best directing, while Sweeney's recording earned her a Grammy nomination for best comedy album.

Sweeney has also appeared on the big screen in Pulp Fiction, Clockstoppers, Whatever It Takes, and Stuart Little. A veteran of live television, Sweeney made her mark on primetime television as a series regular on George & Leo and Maybe It's Me and she guest starred on 3rd Rock from the Sun, Hope & Gloria, Mad About You, and According to Jim. In 2004, Sweeney co-starred in two episodes of Frasier, and had a guest part on Sex and the City. She also served as a consultant on Sex and the City for its last three seasons.

Among Sweeney's more recent stage work is the one-woman show In the Family Way, which started on stage in NYC in early 2003 at the Ars Nova Theatre, and has since migrated to the Groundlings Theatre in Los Angeles. In the Family Way chronicles the adoption of her daughter from China, which she is adapting as a pilot for Warner Bros.

Sweeney's 1993 impression of Chelsea Clinton caused somewhat of a stir when Hillary Clinton found it offensive and sent an angry letter to Studio 8H. Sweeney was a featured player on SNL from 1990-91 and a cast member from then until 1994. She is a cervical cancer survivor.

Sweeney is an atheist, something she brought to light in a one-woman show entitled Letting Go of God. In it, she discusses her Irish Catholic upbringing, early religious ideology, and the life events and internal search that led her to the realization that the universe works fine without a God in charge of it. In 2006, she was awarded the Richard Dawkins Award.