Influenced by Richard Burton, he decided to study at College of Music and Drama and graduated in 1957. In 1965, he moved to London and joined the National Theatre, invited by Laurence Olivier, who could see the talent in him. In 1967, he made his first film for television, A Flea in Her Ear (1967) (TV). From this moment on, he enjoyed a successful career in cinema and television. In 1968, he worked on The Lion in Winter (1968). In 1977, he appeared in A Bridge Too Far, and in 1980, he worked on The Elephant Man.

In the 1990s, Hopkins made movies like Desperate Hours (1990) and Howards End (1992), The Remains of the Day (1993) (nominee for the Oscar), Legends of the Fall (1994), Nixon (1995) (nominee for the Oscar), Surviving Picasso (1996), Amistad (1997) (nominee for the Oscar), The Mask of Zorro (1998), Meet Joe Black (1998) and Instinct (1999). His most remarkable film, however, was The Silence of the Lambs (1991), for which he won the Oscar for Best Actor and also a BAFTA.