Culkin was born in New York City, the son of Patricia Brentrup and Christopher 'Kit' Culkin, a former stage actor with a long career on Broadway.

He has four brothers, Shane Arliss (b. 1976), Macaulay Carson Culkin (b. 1980), Christian Patrick (b. 1987), and Rory Hugh Culkin (b. 1989), and two sisters, Dakota Ulissa (1978-2008) and Quinn Kay (b. 1984).

Kieran Culkin's first film role was a small part alongside his brother, Macaulay, in Home Alone as cousin Fuller McCallister. He continued acting as a child and teenager, mainly working in comedies, including Home Alone 2: Lost in New York and Father of the Bride and its sequel.

As a teenager, he alternated between lead roles in independent films and small parts in mainstream films. He played the title role in the film Igby Goes Down, for which he was nominated for a Golden Globe Award. He appeared in the Academy Award-nominated movie Music of the Heart as well.

He played Buff in Eric Bogosian's updated version of SubUrbia at the Second Stage Theatre in New York. In 2010, Culkin played Scott Pilgrim's "cool gay roommate" Wallace Wells in the movie Scott Pilgrim vs. the World.

He also had the lead role in The Mighty as Kevin Dillon.