Pearce received international attention for his breakout roles in The Adventures of Priscilla, Queen of the Desert (1994), Ed Exley in Curtis Hanson's crime noir L.A.

Confidential (1997) and a man suffering short-term memory loss in Christopher Nolan's psychological thriller Memento (2000).

He also acted in numerous films such as The Time Machine (2002), The Count of Monte Cristo (2002), Bedtime Stories (2008), The Road (2009), The Hurt Locker (2009), The King's Speech (2010), Lawless (2012), and Mary Queen of Scots (2018).

He portrayed Peter Weyland in Prometheus (2012) and Alien: Covenant (2017), and acted in the Marvel Cinematic Universe playing Aldrich Killian in the film Iron Man 3 (2013).

He lived in Box Hill North, Victoria in the late 1980s while working on the Australian drama series Neighbours.

Pearce also found roles in other television series such as Home and Away (1988) and Snowy River: The McGregor Saga (1993).

Pearce portrayed pop artist Andy Warhol in Factory Girl and Harry Houdini in Death Defying Acts.

[10] He performed in the Melbourne Theatre Company's production of Poor Boy, a play with music, co-written by Matt Cameron and Tim Finn.

Pearce starred as the eponymous lead in the Australian TV miniseries Jack Irish, an adaptation of the detective novels of author Peter Temple broadcast on the ABC network in 2012.

Pearce recorded the soundtrack for A Slipping-Down Life, singing and playing guitar on cover versions of songs by Ron Sexsmith, Vic Chesnutt and Robyn Hitchcock.

[22] Pearce has supported charitable organisations related to animal conservation and habitat preservation,[23] as well as publicly expressing his solidarity with the Palestinian people during the Israeli-Palestinian conflict.

[24] On 18 September 2011, Pearce won the Primetime Emmy Award for Outstanding Supporting Actor in a Miniseries or Movie for his work in Todd Haynes' limited series Mildred Pierce as Monty Beragon.