Born in born in Natal, South Africa, he was the son of a sergeant in the mounted police and an actress. His parents separated when he was young and his mother took him to England, and then to Ireland. Cusack's mother and her partner, Breifne O'Rorke, joined the O'Brien and Ireland Players. Cyril made his first stage performance at the age of seven. Cusack was educated in Newbridge College, Newbridge, Co. Kildare, and University College, Dublin. He left without a degree and joined the Abbey Theatre in 1932. Between then and 1945 he performed in over sixty productions, particularly excelling in the plays of Sean O'Casey. In 1947, Cusack formed his own company and staged productions in Dublin, Paris and New York.

In 1963, he joined the Royal Shakespeare Company in London, England and appeared there for several seasons. By this stage he had established a successful career in films.

Cusack was twice married:'s first wife,

1) Maureen Kiely Cusack, an actress, died in 1977, with whom he had three daughters and two sons 2) Mary Rose Cunningham (1979-1993), with whom he had a daughter. He received honorary doctorates in 1977 and 1980 from the NUI and the University of Dublin respectively. In 1984, he appeared as the shop-keeper and Thought Police spy "Charrington" in the film version of George Orwell's Nineteen Eighty-Four. In 1989, he appeared in the film My Left Foot, which won its stars Daniel Day-Lewis and Brenda Fricker Oscars as "Christy Brown" and his mother.

Cusack's last stage performance was in Chekhov's The Three Sisters, in which three of his daughters played the sisters. His four daughters, Niamh, Sorcha, Sinéad and Catherine are actresses. His sons, Paul Cusack and Pádraig Cusack, work as a producer with RTÉ and in computers, respectively.

In 1993, Cyril Cusack died in London, England of motor neurone disease.