Most famous for his work with Alan Moore, he is one of the few artist to have done so many projects with Moore. Miracleman, Swamp Thing and 1963 being the three series best know series. He has also worked with Moore on the Real War Stories anthology and the America's Best Comics 64 Page Giant.

During his run on Swamp Thing he would help co-created Vertigo's flagship character: John Constantine. Alan Moore scripted issue #37 of The Saga of Swamp Thing in which both John and Steven R. Bissette wanted to draw someone who looked like singer Sting from the rock band The Police.

John Totleben is barely active now as an artist. He developed an eye condition which has made him legally blind. He is not completely blind, it is more like tunnel vision where he only has his central vision. Because he can still see he can still make art, however it is more time consuming.