After a short courtship, Morse married Actress Sydney Sturgess on 26 March 1939, during their work together in repertory theatre in Peterborough, Cambridgeshire. The couple had two children, Melanie Morse (1945–2005) and Hayward Morse (b. 1947).

Morse was a member of repertory theatre companies in Peterborough, Nottingham and other cities where he gained experience as an actor while playing more than 200 roles. In 1941 he joined the national tour of The First Mrs. Fraser starring Dame Marie Tempest and A.E. Matthews. He debuted on the London West End stage in The School for Slavery. Other West End productions included Escort, The Assassin and A Bullet in the Ballet. He was directed by John Gielgud in Crisis in Heaven. Morse developed a theatrical partnership with Actress Nova Pilbeam, and they worked together both in film and on stage, most notably in the hit stage productions of The Voice of the Turtle and Flowers for the Living.

Morse made his film debut in the 1942 comedy The Goose Steps Out starring Will Hay and continued with roles in Thunder Rock, When We Are Married and This Man is Mine (released as A Soldier for Christmas in North America) with Glynis Johns and Nova Pilbeam. Other notable films include Kings of the Sun with Yul Brynner, Justine, and Puzzle of a Downfall Child with Faye Dunaway. He also appeared in the thrillers Asylum (1972) with Peter Cushing, Funeral Home with Kay Hawtrey and Lesleh Donaldson, (1980), and The Changeling with George C. Scott (1980). He worked on several Lacewood animated productions, notably as the voice of Dragon in The Railway Dragon, alongside Tracey Moore who played Emily. In 1999 he filmed the dramatic comedy Taxman with Billy Zane, released as Promise Her Anything and on DVD as Nothing to Declare. His final film appearance was in I Really Hate My Job, released in 2007.

In 1951, the Morse family moved to Canada, where he worked in radio and theatre, and participated in the first television broadcasts of CBC Television from Montreal, and later Toronto. Morse became a Canadian citizen in 1953.

He first presented a version of his one-man show Merely Players in 1959, which explored the experiences of actors through history, with the definitive version of the show debuting in 1984 for a Canadian national tour. Morse was perhaps the only actor to have performed in every play of william Shakespeare and George Bernard Shaw.

Morse's first television series was Presenting Barry Morse, which aired for thirteen weeks in the summer of 1960 on CBC. Some of his best known television roles included: Lt Philip Gerard on the 1960s series The Fugitive with David Janssen; "Prof. Victor Bergman" in the 1975-76 season of Space: 1999 with Martin Landau, Barbara Bain and Zienia Merton; 'Mr. Parminter' in The Adventurer with Gene Barry; and "Alec 'The Tiger' Marlowe" in The Zoo Gang with Sir John Mills, Lilli Palmer and Brian Keith. In 1982 he played the Reaganesque U.S. President Johnny Cyclops in the satirical sitcom Whoops Apocalypse in the UK and hosted the series Strange But True for the Global and BBC

Morse served as Artistic Director of the Shaw Festival of Canada for the 1966 season and as an Adjunct Professor at Yale Drama School in 1968.

In 1995, he premiered the Elizabeth Sharland play The Private Life of George Bernard Shaw in Toronto, also starring Shirley Knight. The play featured Morse in the role of George Bernard Shaw with ten actresses portraying the various women in Shaw's life. Morse later performed the play in 1997 at the British Theatre Museum in London.

The cause of Parkinson's disease held a special place in Morse's heart as his wife of more than sixty years, Actress Sydney Sturgess, battled the illness for fourteen years before her death in 1999. In later years he also became an advocate for senior citizens in his adopted homeland of Canada.

The book based on his long-running stage play Merely Players - The Scripts was published in 2003. His first autobiography Pulling Faces, Making Noises was released in 2004.

With his son Hayward Morse, he starred in the 2004 North American debut of Bernard and Bosie: A Most Unlikely Friendship by Anthony Wynn, performed at the University of Florida, Sarasota. This two-act stage drama is based on the correspondence between Playwright George Bernard Shaw, played by Morse, and Lord Alfred 'Bosie' Douglas (the intimate friend of Oscar Wilde), played by Hayward.

Stories of the Theatre was published in 2006 and features material from his CBC radio series A Touch of Greasepaint, which aired from 1954 to 1967.

Morse's final radio performance, Rogues and Vagabonds - A Theatrical Scrapbook, aired on internet radio KSAV 7 August and 9 August 2007, prior to being released on compact disc. The hour-long special audio drama was composed of a half-dozen vignettes and performances culled from theatrical history, including william Shakespeare and George Bernard Shaw.

Barry Morse died 2 February 2008 at University College London Hospital, aged 89, after a brief illness.