Brendan Gleeson was born in Dublin in 1955.  After leaving school for a short while, he worked for two years in an office with a health board. He then graduated from University College Dublin and went on to drama school in London at the Royal Academy of Dramatic Art (RADA). After completing the 3 Year Acting Drama Course at RADA, Gleeson worked at the Royal National Theatre, Shakespeare's Globe Theatre, and the Royal Shakespeare Company in Stratford-upon-Avon. He performed in such works of William Shakespeare as King Lear, Richard III, and Hamlet.

Gleeson started his film career at the age of 34. He first came to prominence in Ireland for his role as Michael Collins in The Treaty, a television film broadcast on RTÉ One, and for which he won a Jacob's Award in 1992. He has acted in such films as Braveheart, I Went Down, Michael Collins, Gangs of New York, Cold Mountain, 28 Days Later, Troy, Kingdom of Heaven, Lake Placid, Artificial Intelligence: AI and The Village. He won critical acclaim for his performance as Irish gangster Martin Cahill in John Boorman's 1998 film The General.

Gleeson later went on to portray Collins' one-time nemesis Winston Churchill in Into the Storm. Gleeson won an Emmy Award for his performance. Gleeson played Hogwarts professor Mad-Eye Moody in the fourth, fifth and seventh Harry Potter films.

In 2008 In Bruges and Gleeson's performance enjoyed huge critical acclaim, earning him several nominations including his first Golden Globe nomination. In the movie Gleeson plays a mentor-like figure for Colin Farrell's hitman.