Many studies have reported an increase in mental health problems during post-secondary transition, often originating from high school years. The present study examined how depressive symptoms during the 2 years following the post-secondary transition could be predicted by, on the one hand, school performance, externalized and learning difficulties, and depressive symptoms before the post-secondary transition, and on the other hand, personal factors, family functioning, and adjustment to college after the transition. From a sample of 438 participants (M = 16.20, SD = 0.87) at time point 1, an integrated model was elaborated using structural equation modeling. The statistical analyses showed that the five constructs fit the data well. The path coefficients showed a negative relationship between externalized and learning problems as perceived by the teacher (ELPT) before the transition and academic performance (AP). Personal characteristics (PC) negatively predicted academic adjustment (AC) over time, whereas the path coefficients between the family factor (FF) and AC were not significant over time. ELPT and AP negatively predicted depression at time point 1. At time points 2 and 3, PC positively predicted depression, and depressive symptoms were positively related over time. The percentage of variance accounted for by the depressive symptoms increased over time.