Objective: Framed in Reinforcement Sensitivity Theory, this study examined the moderating effects of mindfulness and moderate-to-vigorous physical activity (MVPA) on the relationship between behavioral inhibition system (BIS) sensitivity and psychological distress in college students. Participants: Undergraduate students (n = 183) at a large public university in the United States were included in the study. Methods: Self-reported BIS sensitivity, mindfulness, MVPA, and psychological distress were examined in November 2021. Results: Findings revealed a positive relationship between BIS sensitivity and psychological distress, however, this relationship was conditional on levels of mindfulness and MVPA. Specifically, increased reports of mindfulness and MVPA related to lower psychological distress for participants with higher than average BIS sensitivity. Conclusions: Mindfulness and MVPA are buffers for university students prone to psychological distress. Identifying diverse strategies that effectively lower psychological vulnerabilities in college students can be used to develop targeted interventions that reduce psychopathology and promote mental health.