Cusack was born in Durban, Natal, South Africa. His mother, Alice Violet (née Cole), was an English Cockney actress and chorus girl, and his father, James Walter Cusack, was an Irish mounted policeman in Natal Province, South Africa. 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, County 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 60 productions, particularly excelling in the plays of Seán O'Casey. In 1947, Cusack formed his own company and staged productions in Dublin, Paris and New York.
In 1963, Cusack joined the Royal Shakespeare Company in London and appeared there for several seasons. By this stage he had established a successful career in films, which had started at the age of eight. Also in 1963, Cusack won a Jacob's Award for his performance in the Telefís Éireann production of Triptych. He received honorary degrees in 1977 and 1980 from the NUI and the University of Dublin respectively.
Cusack, who was bilingual in English and Irish, had a leading part in the controversial Irish language film Poitín (1977).
Cusack's last stage performance was in Chekhov's Three Sisters, in which three of his daughters played the sisters. His four daughters, Sinéad (born 1948), Sorcha (born 1949), Niamh (born 1959) and Catherine (born 1968) are actresses. His sons, Paul Cusack and Pádraig Cusack (born 1962), work as a producer with Radio Telefís Éireann and as an associate producer at the National Theatre, London, respectively.
Cusack was twice married:
The actress Mary Margaret “Maureen” Kiely (1920–18 December 1977), on 5 April 1945, with whom he had three daughters, Sinéad, Sorcha, and Niamh, and two sons, Paul and Padraig. Mary Rose Cunningham (1979–1993); one daughter (Catherine)
In his later life, Cusack became a campaigner for conservative causes in Ireland, notably in his opposition to abortion, where he became a frequent letter-writer to the main liberal Irish newspaper, The Irish Times. His conservative credentials came under scrutiny following his death and the revelation that he had not been faithful in his first marriage, with a long-term mistress, Mary Rose Cunningham, who bore him a daughter, Catherine. Cusack married Cunningham following his first wife's death.
Regarding his religious faith, Cusack commented “Religion promotes the divine discontent within oneself, so that one tries to make oneself a better person and draw oneself closer to God.”
Cusack was a longtime friend of Irish attorney general, Chief Justice and President of Ireland Cearbhall Ó Dálaigh, whom he got to know in University College Dublin in the early 1930s.
In October 1993, Cusack died at his home at age 82 in Burlington Lane, Chiswick, Greater London, from motor neurone disease (known as Lou Gehrig's disease or ALS in North America), one month before what would have been his 83rd birthday. His acting career had lasted an impressive 75 years.
Cusack is the grandfather of Irish Trotskyist TD, Richard Boyd Barrett, and English actor, Max Irons.