The transition to university life is a time of significant lifestyle changes for young adults. The period of first year university is typically associated with poor changes in lifestyle behaviours such as a reduction in moderate-to-vigorous physical activity (MVPA). Understanding predictors of behaviour changes is important to inform programs and interventions. From a theoretical perspective, it may be that mental health relates to MVPA behaviour change, and motivation may mediate the association between mental health and MVPA behaviour change. Data were collected from University of Toronto incoming students at the beginning of their first year of university and near the end of the year. Participants completed self-report evaluations of depression symptoms, self-rated mental health, and motivational regulation at baseline and self-report MVPA was assessed at both baseline and in spring of the first year and residual change score was calculated. The associations were tested using hierarchical linear regression with the mediation macro. Autonomous motivation was a significant mediator of the association between both self-rated mental health (Point Estimate = .07, SE = .03; BCA CI = .02 to .12) depression symptoms (Point Estimate = -.06, SE = .04; BCA CI = -.17 to -.02) and change in MVPA (R2 = .11 and .10, respectively). These findings provide theoretical evidence for the importance of self-determined motivation in predicting MVPA in university students, and highlight the need to potentially identify students at risk for depressive symptoms and low self-rated mental health for targeted physical activity interventions.