Objective: This study examined joint trends over time in associations between substance use (heavy drinking, cannabis, and cigarette smoking) and mental health concerns (depression, anxiety, and suicidal ideation) among US post-secondary students. Participants: Data came from 323,896 students participating in the Healthy Minds Study from 2009 to 2019, a national cross-sectional survey of US post-secondary students. Weighted two-level logistic regression models with a time by substance interaction term were used to predict mental health status. Results: Use of each substance was associated with a greater odds of students endorsing depression, anxiety, and suicidal ideation. Over time, the association with mental health concerns strengthened substantially for cannabis, modestly for heavy drinking, and remained stable for smoking. Conclusion: Given co-occurrence is common and increasing among post-secondary students, college and university health systems should prioritize early identification, psychoeducation, harm-reduction, and brief interventions to support students at risk.