Polysubstance use in adolescence is a known precursor to chronic substance misuse. Identifying risk factors for polysubstance use is necessary to inform its prevention. The present study examined the association of elevated levels of multiple mental health symptoms with adolescents' engagement in polysubstance use (past month use of alcohol, cigarettes, and marijuana). In a US national sample of 8th, 10th, and 12th grade students from Monitoring the Future surveys, we estimated probability of polysubstance use associated with high levels of depressive symptoms (DS), conduct problems (CP), or both. DS and CP, alone and particularly in combination, were associated with drastically elevated probability of polysubstance use. Adolescents with high levels of both DS and CP had the highest probability of polysubstance use. Among 8th and 10th graders, probability of polysubstance use associated with co-occurring mental health problems was significantly higher for girls than boys.