Early in his career, Gregson-Williams held a position in the 1980s as a music teacher to pupils at the Amesbury School in Hindhead, Surrey, England (his brother Rupert, also a film composer, also taught at Amesbury School during this period). He later taught music at the Guildhall School of Music & Drama, where he had been a pupil, and also for a short period in both Egypt and Africa.
Gregson-Williams has scored a number of motion pictures including Kingdom of Heaven, The Chronicles of Narnia: The Lion, the Witch and the Wardrobe and its sequel The Chronicles of Narnia: Prince Caspian, Sinbad: Legend of the Seven Seas, 'The Rock, Shrek, Chicken Run, Spy Game, Man on Fire, X-Men Origins: Wolverine, and Team America: World Police.
Gregson-Williams has composed the music for Metal Gear Solid 2: Sons of Liberty, Metal Gear Solid 3: Snake Eater, and Metal Gear Solid 4: Guns of the Patriots. He also worked on the music for Metal Gear Solid V: Ground Zeroes along with composer, Ludvig Forssell. His arrangement of the original "Metal Gear Solid Main Theme" was one of the many tracks he created for the Metal Gear Solid games that involved both orchestral and electronic textures.
Hideo Kojima decided to choose him to do the music for Metal Gear Solid 2 after seeing the film The Replacement Killers and felt that the music was perfect for the game.