I wasn't frightened of people, but I didn't have a clue about the adult world.

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.