The COVID-19 pandemic has posed notable challenges to post-secondary students, causing concern for their psychological well-being. In the face of school closures, academic disruptions, and constraints on social gatherings, it is crucial to understand the extent to which mental health among post-secondary students has been impacted in order to inform support implementation for this population. The present meta-analysis examines the global prevalence of clinically significant depression and anxiety among post-secondary students during the COVID-19 pandemic. Several moderator analyses were also performed to examine sources of variability in depression and anxiety prevalence rates. A systematic search was conducted across six databases on May 3, 2021, yielding a total of 176 studies (1,732,456 participants) which met inclusion criteria. Random-effects meta-analyses of 126 studies assessing depression symptoms and 144 studies assessing anxiety symptoms were conducted. The pooled prevalence estimates of clinically elevated depressive and anxiety symptoms for post-secondary students during the COVID-19 pandemic was 30.6% (95% CI: 0.274, 0.340) and 28.2% (CI: 0.246, 0.321), respectively. The month of data collection and geographical region were determined to be significant moderators. However, student age, sex, type (i.e., healthcare student vs. non-healthcare student), and level of training (i.e., undergraduate, university or college generally; graduate, medical, post-doctorate, fellow, trainee), were not sources of variability in pooled rates of depression and anxiety symptoms during the pandemic. The current study indicates a call for continued access to mental health services to ensure post-secondary students receive adequate support during and after the COVID-19 pandemic.