The eldest of three sisters, Shirley Henderson was born into a working-class family in the village of Kincardine in Fife, Scotland. As a teenager she sang locally and performed in school drama clubs. Her first break came when she watched a singer on the Opportunity Knocks TV talent program and decided she could do as well. She entered and won a talent competition at Butlins Holiday Camp and from there graduated to local music club gigs. She was later accepted by London's Guildhall School of Music and Drama. She performed on stage in England's National Theatre company, which led to a role on the British TV drama Hamish Macbeth with future Trainspotting co-star Robert Carlyle.



Being age 35 at the time that she first played Moaning Myrtle, she is the oldest actor to play a Hogwarts student in the Harry Potter films. In 2005 she was runner-up for the Golden Needle at the Seattle International Film Festival for Frozen (2004). In 2005 she was runner-up for Best Actress at the Film de Femmes Creteil for Frozen (2004). In 2004 she won the Bowmore/Scottish Screen/Sunday Times Actress of the Year for American Cousins (2003), intermission (2003) and Wilbur Wants to Kill Himself (2002). In 2003 she won the Silver Plaque at the Chicago International Film Festival for Fishy (2003). In 2002 she won a nomination for the Bowmore/Scottish Screen/Sunday Times Actress of the Year for The Claim (2000) and Bridget Jones's Diary (2001). In 2003 she won a nomination for the Bowmore/Scottish Screen/Sunday Times Actress of the Year for Twenty-four Hour Party People (2002), Once Upon a Time in the Midlands (2002), Villa des Roses (2002) and Harry Potter and the Chamber of Secrets (2002). In 2005 she was awarded Best Actress in a Scottish Film by the BAFTA Awards Scotland for Frozen (2004). She is the only actress to have won Best Actress at Cherbourg-Octeville twice.