Spence is most known for his roles as the Gyro Captain in Mad Max 2 and as Jedediah the pilot in Mad Max Beyond Thunderdome, and as "Zedd" (Zeddicus Zu'l Zorander) in Legend of the Seeker.

He also performed the voice of Chum in Finding Nemo, the Mouth of Sauron in The Lord of the Rings: The Return of the King, the Trainman in The Matrix Revolutions and Tion Medon in Star Wars: Episode III - Revenge of the Sith.

At 1.99 m (6 ft 6 1⁄2 in), Spence is one of the tallest actors to have played a leading role.

He acted as the paleontologist (Huxley) alongside fellow actor Felix Nobis, in the Australian performance of BBC's Walking with Dinosaurs: The Live Experience. In his role, Spence narrates the activities of life-sized mechanical dinosaurs operated by teams of puppeteers and drivers.

In 2008, Spence joined the television series Legend of the Seeker, based on the Sword of Truth series by Terry Goodkind, in the role of Zeddicus Zu'l Zorander, co-starring Craig Horner and Bridget Regan. In November 2009 it began its second 22-episode season (2009-10).