He appeared twice in Doctor Who: in the stories The Claws of Axos (1971) and The Masque of Mandragora (1976).

Pigott-Smith worked in the theatre in Shakespearean and Greek roles; for instance, he played Posthumus in John Barton's 1974 production of Cymbeline for the Royal Shakespeare Company. In early stage roles he is credited as "Tim Smith".

After a long career in smaller roles, Pigott-Smith's appearance as Arthur Llewellyn Davies in the BBC's The Lost Boys mini-series led to his gaining his big break with the leading role of Ronald Merrick in the 1984 television serial The Jewel in the Crown. Other appearances include the title role in the crime drama series The Chief (1990–1993), a recurring role in ITV drama The Vice as Ken Stott's nemesis, Vickers, and Bloody Sunday. He appeared in two adaptations of Elizabeth Gaskell's North and South; in the 1975 version he played Frederick Hale and in 2004 he played Frederick's father Richard. In 1995, he starred in a serial of the series Ghosts.

Pigott-Smith won the BAFTA Award for Best Actor in 1985, for his role in The Jewel in the Crown. In 2014–15, he was nominated for the Laurence Olivier Award and the Tony Award for his lead role in the play King Charles III. He was appointed an Officer of the Order of the British Empire (OBE) in the 2017 New Year Honours for services to drama.

His film career included the 2004 film Alexander, The Four Feathers, Clash of the Titans, Gangs of New York, Johnny English, The Remains of the Day and V for Vendetta. He also appeared as Major General Robert Ford in Director Paul Greengrass's Bloody Sunday (2002), and as the Foreign Secretary in the James Bond film Quantum of Solace (2008). In February 2010 Piggott-Smith played Alan Keen in the television film On Expenses. He also had a cameo appearance as Sniggs in the BBC production of Evelyn Waugh's Decline and Fall in 2017. His final film role was that of Sir Henry Ponsonby, Queen Victoria's Private Secretary, in Victoria & Abdul (2017).

He was a regular narrator of documentary television series. He narrated the Battlefield series, which examines pivotal battles of the Second World War from an operations point of view. Later, he narrated a series on the British Royal Family, entitled Monarchy: The Royal Family at Work. The series followed Queen Elizabeth II for more than a year, including the 2007 state visit to the United States.

Contemporary works included Enron, playing Ken Lay, for the Chichester Festival Theatre, and then London, in 2009 and Tobias in A Delicate Balance at the Almeida Theatre, London in 2011. He returned to the Almeida in 2014 as a post-accession Charles, Prince of Wales in King Charles III, for which he received a nomination for the Olivier Award for Best Actor, and his first Tony Award nomination for its production on Broadway in 2015. He also appeared as Charles in the 2017 film adaptation of the play.

In 2011 he took the title role in King Lear at the West Yorkshire Playhouse, Leeds.

He wrote two children's books in the series The Baker Street Mysteries, featuring the exploits of Sherlock Holmes' Baker Street Irregulars – The Dragon Tattoo (2008) and Shadow of Evil (2009). He played Holmes in a BBC Radio adaptation of The Valley of Fear.

He appeared in Lewis in 2015 as a taxidermist in the episode "One For Sorrow". He also appeared on the ITV series, Downton Abbey in the third series' (third season) fifth episode as obstetrician/gynaecologist Sir Philip Tapsell, who was present at the death of Lady Sybil Crawley Branson (Jessica Brown Findlay) from eclampsia after giving birth to her daughter.

Pigott-Smith died suddenly on 7 April 2017, aged 70. He had been scheduled to appear in a touring production of Death of a Salesman, with opening night in Northampton only three days later. His wife Pamela Miles was also to appear in the play but she had withdrawn after breaking a bone and needing surgery. On 2 May 2017 Coroner for Northamptonshire Anne Pember confirmed she ruled that Mr Pigott-Smith died of natural causes and therefore she will not hold an inquest into his death.