After appearing in several plays, she moved to Los Angeles, California and in 1987 got her first break in a role in Walt Disney's made-for-TV film Student Exchange. Tierney's first starring role in a film was in a low-budget, independently-produced film called Dead Women in Lingerie, shot in 24 days. The film, a thriller with opening and closing credits paying tribute to illegal immigrants post-1986, never received a theatrical release, though it was released on DVD in 2005.

Tierney continued winning small roles in film and television, though it was not until her leading role in NewsRadio from 1995–1999 that she received regular national exposure. While a NewsRadio cast member she also appeared in two ~$100 million films (Primal Fear and Forces of Nature), and the even more successful Jim Carrey film Liar Liar.

After NewsRadio was cancelled, Tierney decided not to pursue a role in another sitcom: When NewsRadio got canceled, ... I thought, there's probably not gonna be something like [that show] again for me...So then, when ER called,...that was a way to stay in [television] that would remain interesting for me. Tierney played Nurse Abigail "Abby" Lockhart on ER, a character that began as a guest appearance as an OB nurse, then expanded in 2000 to a full-time regular part as an ER nurse. Within a year, her work on ER had earned her an Emmy Award nomination, recognition she credits to a "juicy" story arc featuring her and Sally Field[2] Tierney's character Abby Lockhart graduated from medical school and became a doctor at the end of the 2003–2004 season. Since then, her character has gone on to become the female lead on the show.

As of 2007 Tierney's highest-profile film since joining the cast of ER was the 2002 film Insomnia. That same year she also starred in Scotland, Pa., portraying a Lady Macbeth-like character written specifically for her by writer/director and then-husband Billy Morrissette. She also collaborated with NewsRadio writer Joe Furey for a special "Working with Joe Furey" featurette for Furey's film Love and Support.

In 2004, Tierney won the second season tournament of Bravo's Celebrity Poker Showdown against Lauren Graham The show was hosted by Dave Foley, who was her co-lead and romantic interest in NewsRadio. Graham also guest-starred in four episodes of NewsRadio at the beginning of the show's fourth season.

She returned to the stage in May 2006 in an appearance opposite Eric McCormack in the off-Broadway U.S. premiere of Some Girl(s).[7] She also appeared in the 2008 films Semi-Pro, Baby Mama and Finding Amanda.

Tierney was born and raised in the Hyde Park neighborhood of Boston, Massachusetts. Her mother, Pat, is a real estate agent in Boston. Her father, Joseph Tierney, was a prominent Boston politician who served on the Boston City Council for 15 years. Tierney is of Irish descent. She attended Notre Dame Academy in Hingham, Massachusetts, where her studies included drama and led to her appearance at the Boston Globe Drama Festival. After graduation, she attended New York University, and studied drama at Circle-in-the-Square Theatre School.

Tierney married actor-director Billy Morrissette in February 1993, after the two met on the set of a never-aired television series. She filed for divorce 13 years later, citing irreconcilable differences.