The longstanding debate over human contribution to Pleistocene megafauna extinctions motivates our examination of plausible hunting behaviors that may have impacted prey populations. Prey size declines during the Pleistocene have been proposed as a unifying selecting agent of human evolution. Here, we identify prey selection criteria and exploitation patterns that could have increased the extinction risk for targeted species. Limited protein metabolism capacity in humans is proposed to have led to a focus on fat-rich prey, primarily large and prime adults, and selective exploitation of fatty body parts. Such behaviors may have made human-hunted species more vulnerable to population decline due to human predation alone or in combination with environmental changes. We contextualize this hypothesized mechanism within modern evolutionary theory, noting alignment with Niche Construction Theory as an explanation for the directional changes in human physiology and culture over time. The well-evidenced trend of brain expansion provides historical continuity with longer-term primate evolution, meeting recent calls for greater emphasis on ancestral connections in evolutionary models. Display omitted •Humans contributed to prey extinction, targeting fat to mitigate a protein constraint.•Large prey was fatter but more sensitive to hunting pressure than smaller prey.•Prime adult prey, critical to population growth, was fatter than young and old.•Wasteful consumption of fatty parts at dry/snowy seasons added population pressure.•Smaller prey niche construction explains human evolution.