The COVID-19 pandemic introduced significant disruptions in the learning environment for many post-secondary students. While emerging evidence suggest mental health has declined during the pandemic, little is known about how the pandemic has affected students academically. This study investigates how COVID-19 psychological distress impacts academic performance among a Canadian sample of post-secondary students (n = 496). Path analysis findings suggest that greater levels of COVID-19 distress was associated with lower self-reported predicted GPA. Metacognitive, motivational, and social and emotional challenges emerged as the most salient challenge areas that fully mediated the relationship between COVID-19 psychological distress and self-reported predicted GPA. Specifically, COVID-19 distress predicted greater levels of metacognitive and motivational challenges which, in turn, predicted lower self-reported GPA. Similarly, greater levels of COVID-19 distress predicted more social and emotional challenges but these challenges were associated to higher perceived GPA. Findings warrant future research to help students manage and cope with academic challenges that may be exacerbated under stressful conditions.