I spend plenty of time in London and it doesn't scare me, but it's a lonely place, even if you've got friends there. My job takes me all around the world, meeting lots of interesting people. But I think if I couldn't get home, if I couldn't get back to what I consider my real life I'd be frightened.

Henderson then moved into films playing Morag in Rob Roy (1995) and Spud's girlfriend Gail in Danny Boyle's Trainspotting (1996). Having joined an after-school drama club Henderson attended Fife College at the age of 16 where Shirley Henderson completed a one-year course resulting in a National Certificate in Theatre Arts. She continued her work in the theatre including many productions at the National Theatre in London.

She is perhaps best known for her roles as Gail in Trainspotting Jude in Bridget Jones's Diary and Moaning Myrtle in Harry Potter and the Chamber of Secrets and Harry Potter and the Goblet of Fire.