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The COVID-19 pandemic has elicited increased sedentary behaviors, decreased moderate-to-vigorous physical activity (MVPA), and worsened mental health, yet the longitudinal impact of these changes and their inter-relations remains unknown. Our purpose was to examine associations between changes in self-reported activity behaviors and mental health over an 8-week period following the COVID-19 outbreak. Participants from all 50 states and the District of Colombia were recruited through convenience and snowball sampling at baseline April 3–10, 2020. Prospective data from 2,327 US adults with ≥2 responses (63.8% female; 74.3% response rate) were collected weekly via online survey for eight consecutive weeks (April 3–June 3, 2020). Primary exposures were self-reported time spent sitting, viewing screens and in MVPA, with primary outcomes being depressive symptoms, anxiety symptoms, and positive mental health (PMH). A significant sitting-by-time interaction ( p  < 0.05) showed slightly higher marginal effects for depressive symptoms for the 90th-percentile of sitting time than the 10th-percentile at baseline (5.8 [95% confidence interval = 5.5–6.2] vs. 5.7 [5.4–6.1]), with the difference magnifying over time (week 8: 3.5 [3.2–3.9] vs. 2.7 [2.4–2.9]). No other interactions over time were significant. Screen time was negatively associated with PMH and positively associated with depressive and anxiety symptoms ( p  < 0.05). Sitting time was negatively associated with PMH ( p  < 0.05). Rapid changes in sitting patterns (e.g., due to a pandemic) may have lasting effects on depressive symptoms. Strategies targeting those most affected (i.e., young adults, females) and/or focused on reducing sitting time may be critical for preventing long-term mental health effects resulting from COVID-19 or other large-scale behavior changes in the general population.

High Sitting Time Is a Behavioral Risk Factor for Blunted Improvement in Depression Across 8 Weeks of the COVID-19 Pandemic in April–May 2020