This project evaluated the impact of COVID-19-related public health restrictions on physical activity, sedentary time, mental health, and their interrelations. Cross-sectional data were collected from 3,052 US adults on April 3rd-7th, 2020. Physical activity, sitting, and screen time, both pre- and post-COVID-19-related restrictions, along with currently-followed public health restrictions and current mental health were self-reported. Participants were grouped by meeting physical activity guidelines, ≥8 hrs/day of sitting, or ≥8 hrs/day of screen time. Physical activity was reduced by 32.3% among previously active participants but largely unchanged among previously inactive participants. No longer being active and increased screen time following COVID-19-related restrictions were associated with worse current mental health. Self-isolation/quarantine was associated with higher depressive and anxiety symptoms compared to social distancing. Concerted efforts to maintain and enhance physical activity participation and limit screen time during pandemic-related public health restrictions are needed to mitigate short- and likely long-term mental health consequences.