Irons's first major film role came in the 1981 romantic drama The French Lieutenant's Woman, for which he received a BAFTA nomination for Best Actor. After starring in such films as Moonlighting (1982), Betrayal (1983), and The Mission (1986), he gained critical acclaim for portraying twin gynecologists in David Cronenberg's psychological thriller Dead Ringers (1988). In 1990, Irons played accused murderer Claus von Bulow in Reversal of Fortune, and took home multiple awards including an Academy Award for Best Actor. Other notable films have included The House of the Spirits (1993), The Lion King (1994), Die Hard with a Vengeance (1995), Lolita (1997), The Merchant of Venice (2004), Being Julia (2004), and Appaloosa (2008).
Irons has also made several notable appearances on television. He earned his first Golden Globe Award nomination for his breakout role in the ITV series Brideshead Revisited (1981). In 2006, Irons starred opposite Helen Mirren in the historical miniseries Elizabeth I, for which he received a Golden Globe Award and an Emmy Award for Best Supporting Actor. Since 2011, he has been starring in the Showtime historical drama The Borgias.