Most of Australia's largest mammals became extinct 50,000 to 45,000 years ago, shortly after humans colonized the continent. Without exceptional climate change at that time, a human cause is inferred, but a mechanism remains elusive. A 140,000-year record of dietary δ13C documents a permanent reduction in food sources available to the Australian emu, beginning about the time of human colonization; a change replicated at three widely separated sites and in the marsupial wombat. We speculate that human firing of landscapes rapidly converted a drought-adapted mosaic of trees, shrubs, and nutritious grasslands to the modern fire-adapted desert scrub. Animals that could adapt survived; those that could not, became extinct.