During the COVID-19 pandemic, social distancing measures often result in individual isolation, which can lead to adverse mental outcomes. We collected online questionnaires from 3,952 US adults to examine the impact of "shelter-in-place" guidelines on mental health, and to explore potential disparities and modifiable factors. Self-reported anxiety, depression, and PTSD symptoms were associated with more restrictive quarantine. Younger adults, women, those with lower income, more insecurity, more media exposure, reduced physical activity, or worsened family relationships were particularly affected. Targeted prevention on susceptible subpopulations, including young adults and lower SES groups, might help mitigate disparities in COVID-19-related mental health problems.