Tierney was born and raised in the Hyde Park neighborhood[3] of Boston, Massachusetts, the eldest of three children in an Irish American Catholic family.

[6] After appearing in several plays, Tierney moved to Los Angeles in 1987, beginning with a role in Disney's made-for-TV film Student Exchange.

Within a year, Tierney's work on ER earned her an Emmy Award nomination, a recognition she credits to a "juicy" story arc featuring Sally Field as Lockhart's mother Maggie Wyczenski, who has bipolar disorder.

That same year, she also starred in Scotland, Pa. where she portrayed a Lady Macbeth–like character written specifically for her by Billy Morrissette, her husband at the time.

In 2004, Tierney won the second-season tournament of Celebrity Poker Showdown against Lauren Graham, who had a guest role in the fourth season of NewsRadio.

[12] Tierney's role in the series, a legal drama produced by Jerry Bruckheimer, marked her return to television after recovering from breast surgery and cancer treatments.

Tierney herself conceived the idea for this play, which recreates a raucous debate on Women's Liberation that Norman Mailer organized with prominent feminists in 1971.

[16] In February 2011, Tierney made her debut at the Gate Theatre in the Dublin premiere of Yasmina Reza's God of Carnage (translation by Christopher Hampton) alongside Ardal O'Hanlon.

[21] In 2018, Tierney co-starred with Steve Carell and Timothée Chalamet in the dark family drama film Beautiful Boy, based on the memoir of the same name by David Sheff.

[22] In 2019, Tierney appeared in The Report as "an intense, driven, somewhat vengeful Counterterrorism expert determined to get behind any program that promises to get the intel that will stop another attack from happening.

"[23] Also in 2019, Tierney originated the lead role of Elizabeth in the West Coast premiere of Jen Silverman's play Witch at the Geffen Playhouse, directed by Marti Lyons.