Coulouris was born in Manchester, Lancashire, England, the son of Abigail (née Redfern) and Nicholas Coulouris, a merchant of Greek origin. He was brought up both in Manchester and nearby Urmston and was educated at Manchester Grammar School. He attended London's Central School of Speech and Drama, in the company of fellow students Laurence Olivier and Peggy Ashcroft.
Coulouris made his stage debut in 1926 with Henry V at the Old Vic. By 1929, he made his first Broadway appearance, followed by his first Hollywood film role in 1933.
A major impact on his life was Orson Welles, whom he met in 1936 when they both had roles in the Broadway production of Sidney Kingsley's Ten Million Ghosts. Welles invited Coulouris to become a charter member of his Mercury Theatre, and in 1937 Coulouris performed the role of Mark Antony in the company's debut production, Caesar, an innovative modern-dress production of Shakespeare's Julius Caesar.
"Even 'Friends, Romans, countrymen' sounds on his tongue as if it were a rabble-rousing harangue he is uttering for the first time," noted John Mason Brown in the New York Post.
In 1938, he appeared in the Mercury stage productions of The Shoemaker's Holiday and Heartbreak House, and became part of the repertory company that presented CBS Radio's The Mercury Theatre on the Air and its sponsored continuation, The Campbell Playhouse (1938–40).
In Citizen Kane (1941), Coulouris played Walter Parks Thatcher, a financier similar to J. P. Morgan. Coulouris and Welles each received a 1941 National Board of Review Award for their performances.
During the 1930s and 1940s, Coulouris remained a regular figure on the stage and screen, starring in his own Broadway production of Richard III in 1943. His films in this period included For Whom the Bell Tolls (1943), Between Two Worlds (1944), Mr. Skeffington (1944) and Watch on the Rhine (1943), in which he repeated the role he originated in the Broadway production. He also performed as Robert de Baudricourt in Joan of Arc (1948), starring Ingrid Bergman. While most of his performances are strong ones, usually as a heavy or villain, occasionally he could turn his serious characterizations into humorous ones. Thatcher in Citizen Kane is fussy and pompous at times. A better (if briefer) example was in Mr. Skeffington as Dr. Byles, planning to go on a well-deserved, long-delayed holiday only to find it delayed again by a selfish, impossible Fanny Skeffington (Bette Davis).
Coulouris was the first actor to star in the title role of the Bulldog Drummond programme on the Mutual Broadcasting System.
Coulouris returned to Britain after 1950, living first in Putney and later in Hampstead. He appeared in more films, theatre and television productions. His stage work was the most well regarded and included the title role in King Lear at the Glasgow Citizens' Theatre (1952); the lead (Dr. Stockmann) in An Enemy of the People (1959) at the Arts Theatre, Cambridge; Peter Flynn in Seán O'Casey's The Plough and the Stars at the Mermaid Theatre (1962); a part in August Strindberg's The Dance of Death; and Big Daddy in Tennessee Williams's Cat on a Hot Tin Roof (1970).
Later film roles included parts in the Doctor in the House (1954), Papillon (1973), Mahler and Murder on the Orient Express (both 1974). During his life he played in over eighty films.
Radio roles were also numerous, and his television roles included parts in Danger Man and The Prisoner ("Checkmate", 1967). Other notable appearances included the reoccurring role of science writer Harcourt Brown in the ABC serials, Pathfinders to Mars and Pathfinders to Venus, which were sequels to earlier serials; Target Luna and Pathfinders in Space. He appeared as Arbitan in the Doctor Who serial The Keys of Marinus (1964).
Coulouris was married to Louise Franklin (1930–1976) and Elizabeth Donaldson (1977–1989) and was the father of computer scientist George Coulouris and artist Mary Louise Coulouris.
Coulouris died in London on 25 April 1989, of heart failure following Parkinson's disease.
In Me and Orson Welles (2008), Richard Linklater's period drama set in the days surrounding the premiere of the Mercury Theatre's production of Caesar, Coulouris is portrayed by Ben Chaplin.
George Coulouris's Broadway credits are listed at the Internet Broadway Database.The Novice and the Duke (9 December 1929 – January 1930) as Friar Peter
The Late Christopher Bean (31 October 1932 – May 1933) as Tallant
Best Sellers (3 May – June 1933) as Julian Mosca
Mary of Scotland (27 November 1933 – July 1934) as Lord Burghley and as Lord Erskine
Valley Forge (10 December 1934 – January 1935) as Lieutenant Cutting
Blind Alley (24 September 1935 – January 1936) as Dr. Anthony Shelby
Saint Joan (9 March – May 1936) as John de Stogumber
Ten Million Ghosts (23 October – November 1936) as Zacharey
Caesar (11 November 1937 – March 1938) as Marc Antony
The Shoemaker's Holiday (1 January – 28 April 1938) as The King
Heartbreak House (29 April – 11 June 1938) as Boss Mangan
Madame Capet (October 1938) as Mirabeau
The White Steed (10 January 1939 –?) as Father Shaughnessy
Cue for Passion (19–28 December 1940) as John Elliott
Watch on the Rhine (1 April 1941 – 21 February 1942) as Teck de Brancovis
King Richard III (24 March – 3 April 1943) as Richard, Duke of Glouchester (Richard III)
The Master Race (1944) American drama as Von Beck
The Alchemist (6–16 May 1948) as Subtle
S.S. Glencairn (20–30 May 1948) as The Donkey Man
The Insect Comedy (3–12 June 1948) as The Vagrant
Beekman Place (7–31 October 1964) as Samuel Holt
The Condemned of Altona (3 February – 13 March 1966)
King Richard III (24 March – 3 April 1943)