Tobacco and cannabis use, alcohol consumption and inactivity are health risk behaviors (HRB) of crucial importance for health and wellbeing. The impact of the COVID-19 pandemic on university students’ engagement in HRB has yet received limited attention. We investigated whether HRB changed during the COVID-19 pandemic, assessed factors associated with change and profiles of HRB changes in university students. A web-based survey was conducted in May 2020, including 5021 students of four German universities (69% female, the mean age of 24.4 years (SD = 5.1)). Sixty-one percent of students reported consuming alcohol, 45.8% binge drinking, 44% inactivity, 19.4% smoking and 10.8% cannabis use. While smoking and cannabis use remained unchanged during the COVID-19 pandemic, 24.4% reported a decrease in binge drinking while 5.4% reported an increase. Changes to physical activity were most frequently reported, with 30.6% reporting an increase and 19.3% reporting a decrease in vigorous physical activity. Being female, younger age, being bored, not having a trusted person and depressive symptoms were factors associated with a change in HRB. Five substance use behavior profiles were identified, which also remained fairly unchanged. Efforts to promote student health and wellbeing continue to be required, also in times of the COVID-19 pandemic.