Many insects enter coma upon exposure to anoxia, a feature routinely exploited by experimentalists to handle them. But the genetic and physiological bases of anoxic coma induction and recovery are only partially understood, as are the long-term consequences for the animal's performance. We examined three populations of Drosophila melanogaster (designated B) that have been inadvertently under selection for rapid recovery from CO2 exposure for nearly 40 years (around 1,000 generations) resulting from routine maintenance practices. We contrasted CO2 and N2 (presumed a less reactive gas) knockdown and recovery times of these B flies with six populations of common ancestry (A and C populations) that were not exposed to CO2 over the same period. We found that B populations showed faster and more consistent locomotor recovery than A or C populations after CO2 knockdown, a result also observed with N2 knockdown. A and C populations showed much higher variance in recovery time after CO2 exposure than after N2 exposure, suggesting gas-specific effects on pathways associated with locomotor recovery. While these selection treatments result in considerable variation in life history attributes and body size, with the characteristic intermediacy of B populations, their superiority in resistance to gas exposure and locomotor recovery suggests that it is a direct consequence of prior repeated exposure to anoxia, broadly, and CO2, specifically. Hence we describe a powerful new evolutionary model for the genetic and physiological investigation of anoxic coma in insects.