This study explored the relationship between cumulative ecological risk exposure and academic burnout among Chinese college students and the mediating and moderating effects of neuroticism and gender, respectively. A total of 580 college students were selected as participants. They completed a battery of questionnaires that measured cumulative ecological risk, neuroticism, and academic burnout. The results showed that: (1) cumulative ecological risk was positively related to neuroticism and academic burnout; (2) cumulative ecological risk positively predicted academic burnout; (3) neuroticism partly mediated the relationship between cumulative ecological risk and academic burnout; and (4) gender moderated the effect of cumulative ecological risk and academic burnout. A high level of cumulative ecological risk had a greater impact on neuroticism among women, compared to men. These findings advance our current knowledge of the specific effects of cumulative ecological risk on academic burnout and the underlying internal mechanisms of this relationship. Furthermore, this study provides a constructive perspective on preventing and reducing academic burnout among college students.