In 1939, Scofield left school at the age of seventeen and began training at the Croydon Repertory Theatre. Shortly after the outbreak of the Second World War, Scofield arrived for a physical examination and was ruled unfit for Service in the British Army. He later recalled, "They found I had crossed toes. I was unable to wear boots. I was deeply ashamed."

Scofield began his stage career in 1940 with a debut performance in American Playwright Eugene O'Neill's Desire Under the Elms at the Westminster Theatre, and was soon being compared to Laurence Olivier. He played at the Old Rep in Birmingham. From there he went to the Shakespeare Memorial Theatre in Stratford, where he starred in Walter Nugent Monck's 1947 revival of Pericles, Prince of Tyre.

Paul Scofield married Actress Joy Parker in October 1942. They had met while he played Hamlet to her Ophelia. Scofield later said, "Joy and I simply decided to be married, we were both of age and were determined. Any doubts from our families were overruled and they were the usual ones – too young, etc. We had a week out at the end of The Moon Is Down tour, married during that week, and went straight into the Whitehall Theatre."

Paul and Joy Scofield had two children: Martin (born 1945) who became a Senior Lecturer in English and American literature at the University of Kent and Sarah (born 1951). When asked by Garry O'Connor how he wished to be remembered, Scofield responded, "If you have a family, that is how to be remembered." Filmmaker Michael Winner once described the Scofields as, "one of the few very happily married couples I've ever met."

Also in 1947, Scofield appeared as Hamlet at the Royal National Theatre alongside a then unknown Claire Bloom as Ophelia. In her later book, Leaving a Doll's House: A Memoir, Bloom recalls that during the production she had a serious crush on Scofield. As Scofield was happily married and the Father of a son, Bloom hoped only "to be flirted with and taken some notice of." She later recalled, "I could never make up my mind which of my two Hamlets I found the more devastating: the openly homosexual, charismatic Helpmann, or the charming, shy young man from Sussex."

Scofield declined the honour of a knighthood on three occasions, but was appointed CBE in 1956 and became a Companion of Honour in 2001. In 2002 he was awarded the honorary degree of D. Litt by the University of Oxford.

Scofield's versatility at the height of his career is exemplified by his starring roles in theatrical productions as diverse as the musical Expresso Bongo (1958) and Peter Brook's celebrated production of King Lear (1962).

Other major screen roles include the Art-obsessed Nazi colonel Von Waldheim in The Train (1964), Strether in a 1977 TV adaptation of Henry James's novel The Ambassadors, Tobias in Edward Albee's A Delicate Balance (1973), Professor Moroi in the film of János Nyíri's If Winter Comes (1980), for BBC Television; Mark Van Doren in Robert Redford's film Quiz Show (1994), and Thomas Danforth in Nicholas Hytner's film adaptation (1996) of Arthur Miller's The Crucible.

He was subsequently the voice of the Dragon in another play by Robert Bolt, a children's drama The Thwarting of Baron Bolligrew. Expresso Bongo, Staircase and Amadeus were filmed with other actors, but Scofield starred in the screen versions of A Man for All Seasons (1966) and King Lear (1971).

In 1969, Scofield became the sixth performer to win the Triple Crown of Acting, winning an Emmy Award for Outstanding Single Performance by an Actor in a Leading Role for Male of the Species.

In a career devoted chiefly to the classical theatre, Scofield starred in many Shakespeare plays and played the title role in Ben Jonson's Volpone in Peter Hall's production for the Royal National Theatre (1977). Highlights of his career in modern theatre include the roles of Sir Thomas More in Robert Bolt's A Man for All Seasons (1960); Charles Dyer in Dyer's play Staircase, staged by the Royal Shakespeare Company in 1966; the definitive Laurie in John Osborne's A Hotel in Amsterdam (1968); and Antonio Salieri in the original stage production of Peter Shaffer's Amadeus (1979).

According to the DVD extras documentary for the film The Shooting Party (1985), in the very first shot of the very first day of filming, all the male lead actors, including Paul Scofield, who was playing Sir Randolph Nettleby, were to come into shot on a horse-drawn shooting brake driven by the renowned film horse-master George Mossman. As they turned the first corner, the plank that Mossman was standing on broke in two and he was hurled forward and down, falling between the sets of wheels and taking the reins with him. He was struck by a horse's hoof and concussed. The horses shied and broke into a gallop.

Actress Helen Mirren, who appeared with Scofield in the 1989 film When the Whales Came, said of him, "He aspires to the soul rather than the character. He has no sense of personal ambition. He's one of our great, great actors. We're lucky to have him."

In 1990, actor and filmmaker Mel Gibson, who played Scofield's son in Franco Zeffirelli's Hamlet, compared the experience to being "thrown into the ring with Mike Tyson."

In 2004, a poll of actors of the Royal Shakespeare Company, including Ian McKellen, Donald Sinden, Janet Suzman, Ian Richardson, Antony Sher and Corin Redgrave, acclaimed Scofield's Lear as the greatest Shakespearean performance ever. Scofield appeared in many radio dramas for BBC Radio 4, including in later years plays by Peter Tinniswood: On the Train to Chemnitz (2001) and Anton in Eastbourne (2002). The latter was Tinniswood's last work and was written especially for Scofield, an admirer of Anton Chekhov. He was awarded the 2002 Sam Wanamaker Prize.

Scofield died from leukemia on 19 March 2008 at the age of 86 at a hospital near his home in rural Sussex, England. His memorial Service was held at Westminster Abbey on 19 March 2009. His wife Joy died four years later on 7 November 2012, aged 90.

When asked about Claire Bloom decades later, Scofield recalled, "Sixteen years old I think – so very young and necessarily inexperienced, she looked lovely, she acted with a daunting assurance which belied entirely her inexperience of almost timid reticence. She was a very good Ophelia."