Social distancing is the most visible public health response to the COVID-19 pandemic, but its implications for mental health are unknown. In a nationwide online sample of 435 U.S. adults, conducted in March 2020 as the pandemic accelerated and states implemented stay-at-home orders, we examined whether stay-at-home orders and individuals’ personal distancing behavior were associated with symptoms of depression, generalized anxiety disorder (GAD), intrusive thoughts, insomnia, and acute stress. Stay-at-home order status and personal distancing were independently associated with higher symptoms, beyond protective effects of available social resources (social support and social network size). A subsample of 118 participants who had completed symptom measures earlier in the outbreak (February 2020) showed increases in depression and GAD between February and March, and personal distancing behavior was associated with these increases. Findings suggest that there are negative mental health correlates of social distancing, which should be addressed in research, policy, and clinical approaches to the COVID-19 pandemic.