This study examined how neighborhood conditions changed and how neighborhood conditions were associated with physical activity and mental health during the COVID-19 pandemic among Americans. The major outcomes were stratified by the neighborhood's poverty and regression models were used to assess the associations between neighborhood conditions and their change during the pandemic and the outcomes of physical activity and mental health. The results show that low-poverty neighborhoods had more health-promoting neighborhood conditions before the outbreak and more positive changes during the outbreak. Health-promoting neighborhood conditions were associated with higher physical activity and moderate physical activity and lack of negative neighborhood conditions such as crime/violence and traffic were associated with a lower risk of mental health problems including loneliness, depression, and anxiety. Mental health problems were also significantly associated with the COVID-19 infection and death and household income level. Our findings suggest that it is plausible that the disparities of physical activity and mental health by neighborhood exacerbate due to the pandemic and people who living in socioeconomically disadvantaged neighborhoods bear increasingly disproportionate burden.