Changes in life history are expected when new sources of extrinsic mortality impact on natural populations. We report a new disease, devil facial tumor disease, causing an abrupt transition from iteroparity toward single breeding in the largest extant carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii), in which males can weigh as much as 14 kg and females 9 kg. This change in life history is associated with almost complete mortality of individuals from this infectious cancer past their first year of adult life. Devils have shown their capacity to respond to this disease-induced increased adult mortality with a 16-fold increase in the proportion of individuals exhibiting precocious sexual maturity. These patterns are documented in five populations where there are data from before and after disease arrival and subsequent population impacts. To our knowledge, this is the first known case of infectious disease leading to increased early reproduction in a mammal. The persistence of both this disease and the associated life-history changes pose questions about longer-term evolutionary responses and conservation prospects for this iconic species.