He began his career by directing and writing several short films, and garnered a Tony Award nomination in 2006 for his role in the Broadway production The Lieutenant of Inishmore.

[1] In 2023, he received a Golden Globe nomination for his role in the limited series The Patient, and also starred in the satirical political miniseries White House Plumbers.

[7] Gleeson appeared on the Broadway theatre show The Lieutenant of Inishmore at age twenty-three, receiving a Tony Award nomination for his role as the dim-witted Davey.

[8][9] In late 2007, Gleeson played Herbert Pocket in the Hugh Leonard adaptation of Charles Dickens's Great Expectations at the Gate Theatre in Dublin.

[17] Also that year, in the film Sensation, Gleeson played the role of a young farmer whose "soulless encounter" with a call-girl "develops into a bittersweet love story".

[21] The multi Academy Award nominated Coen Brothers' film True Grit featured Gleeson as Moon, a young outlaw.

[26] The Daily Telegraph critic Tim Robey praised his performance, saying Gleeson "nails Levin’s adorable self-seriousness without sentimentalising what can make him hard work.

Starring alongside Hayley Atwell, he played a man who is killed in a car crash, but returns to his lover as a synthetic android clone of himself.

"[31] In Lenny Abrahamson's Frank (2014), he portrayed Jon, a wannabe musician who joins the band of the eccentric, papier-mâché head-wearing titular character played by Michael Fassbender.

[32] Gleeson played a small role as a psychotic killer in the Irish drama Calvary, starring his father as a Catholic priest who visits him in prison.

[34] Along with his father and brother Brian, Gleeson created and stars in the Immatürity For Charity comedy sketches, which raise money for the St. Francis Hospice in Raheny, Dublin.

[37] The film stars Gleeson as a programmer who wins a competition to visit the home of his company's CEO (Oscar Isaac) and test the human qualities of the artificially intelligent humanoid robot Ava, who is played by Alicia Vikander.

[44] Alongside his brother Brian and his father Brendan, Gleeson starred in a revival of the Enda Walsh play The Walworth Farce from January to February 2015.

[48] Gleeson then played fictional CIA agent Monty Schafer in American Made, released in September 2017, starring Tom Cruise as drug smuggler Barry Seal.

in which he shared significant screen time with his brother, starred alongside Christina Applegate and Thomas Haden Church in the independent comedy Crash Pad,[50] and portrayed Winnie-the-Pooh creator A.

[53] Gleeson next starred in Peter Rabbit (2018) – based on the stories of the character of the same by Beatrix Potter – as Thomas McGregor, the great-grandnephew and heir to Mr.

[58] The story concerns a country doctor (Gleeson) who takes on a patient living in a possibly haunted old estate, where he falls in love with the owner's youngest daughter (Wilson).

In 2020 he co-starred opposite Merritt Wever in Run, an American comedy thriller television series created by Vicky Jones that premiered on April 12, 2020 on HBO.

[62] In 2021 he starred in Frank of Ireland, an Irish comedy television series that he co-created with his brother Brian Gleeson and close friend, Michael Moloney.

It received its world premiere at Edinburgh International Festival in August 2021 prior to its opening at GIAF 2021 in September and New York transfer to St. Ann’s Warehouse in November.

[66] In 2022, he starred in the FX on Hulu psychological thriller limited series The Patient as Sam Fortner, a serial killer, alongside Steve Carell.

[70] In August 2023 Gleeson starred in the music video for "De Selby (Part 2)" by Irish singer song writer, Hozier.

[74] In January 2024 it was announced that Gleeson had joined the cast of Guy Ritchie's Fountain of Youth opposite John Krasinski and Natalie Portman in an undisclosed role.

[77] In an April 2020 interview with The Guardian, Gleeson stated that it never crossed his mind to change his surname at the beginning of his career to stay out of his father's shadow.

Gleeson is close friends with Irish actors Laurence Kinlan, Tadhg Murphy, Mark Huberman and Paul Reid after meeting on the set of Boy Eats Girl.