Opie emerged as an influential figure in the British art scene of the 1980s after producing a series of painted metal sculptures that humorously combined loosely painted imagery with steel shapes. Portraits and animated walking figures, rendered with minimal detail in black line drawing, are hallmarks of the artist’s style. His themes have been described as "engagement with art history, use of new technology, obsession with the human body" and "work with one idea across different media". When asked to describe his approach, Opie said "I often feel that trying to make something realistic is the one criterion I can feel fairly sure of. Another one I sometimes use is, would I like to have it in my room? And I occasionally use the idea, if God allowed you to show Him one [portrait] to judge you by, would this really be it?"

In 2010, the four-sided LED sculpture Ann Dancing was installed in Indianapolis, as the first artwork on the Indianapolis Cultural Trail.

Opie has also created a monument to singer Bryan Adams. In 2010, he was commissioned by the National Portrait Gallery to create a portrait of the inventor and engineer Sir James Dyson, titled James, Inventor.

Opie has a number of public installations around the world. They include the recently completed Promenade (2012), a permanent installation in Calgary, and a series of glass panels commissioned by St Mary's Hospital, London. Three sculptures from his Caterina dancing naked series were displayed in Great St Helen’s Square, London as part of the Great St Helen's Sculpture Space.