The U-Flourish study includes two large cohorts of first-year undergraduate students studying at Queen’s University. Electronic surveys are completed at the start and end of each academic year. In 2018 and 2019, almost one-third of students screened positive for anxiety and depression at entry to university. Mental health problems increased over the first academic year in both cohorts, were higher in females compared to males, and were associated with lower grades and university well-being. International students reported similar screen positive rates for common mental health problems, but felt less connected and struggled academically compared to domestic students. Lower self-esteem and social support, higher stress, and substance misuse were associated with worse mental health. University connectedness may mitigate risk of persistent or emergent anxiety and depressive symptoms, whereas drug use appears to increase this risk. The U-Flourish survey has proven acceptance and can inform university-based programs and early intervention initiatives.