Introduction: As evidence of the psychological effects of the COVID-19 pandemic emerge, examining the role of self-regulation may yield key insights. This prospective study tested whether pre-pandemic self-regulation was associated with mental health, well-being, and substance use during the initial COVID-19 surge. Methods: Participants (N = 236; M-age = 30.3; 64% female) were assessed 1-3 years prior to the pandemic and again in April of 2020. Markers of self-regulation (vagal tone, attachment insecurity, stress-reactive rumination, and attentional control) were assessed at Time 1, as were depressive symptoms, sleep problems, relationship satisfaction, perceived stress, and substance use. these outcomes were assessed again during the pandemic, along with anxiety symptoms and peri-traumatic distress. Results: Poor pre-pandemic self-regulation was associated with higher peri-pandemic depressive and anxiety symptoms, peritraumatic distress, and cannabis use. Self-regulation was not associated with sleep, relationship satisfaction, alcohol use, or drug use and did not moderate changes over time. Discussion: Prospective analyses indicated simultaneous, independent associations of cognitive and emotional self-regulation with mental health and well-being during the initial COVID-19 pandemic surge, yet prepandemic self-regulation did not account for trajectories of change over time. Findings emphasize the importance of prospective data for understanding biopsychosocial resilience during the pandemic and beyond.