Introduction: We investigated whether changes in engagement in home-based creative activities were associated with changes in depressive symptoms, anxiety symptoms and life satisfaction during the COVID-19 pandemic, aiming to replicate findings from the UK in a USA sample. Methods: 3725 adults were included from the COVID-19 Social Study in the USA, a panel study collecting data weekly during the COVID-19 pandemic. We measured engagement in eight types of creative leisure activities on the previous weekday between April and September 2020. Data were analysed using fixed effects regression models. Results: Increased time spent gardening was associated with reductions in depressive and anxiety symptoms and enhanced life satisfaction. Spending more time doing woodwork/DIY and arts/crafts were also associated with enhanced life satisfaction. However, more time watching television, films or other similar media (not for information on COVID-19) was associated with increased depressive symptoms. Other creative activities were not associated with mental health or well-being. Conclusion: Some findings differ from evidence obtained in the UK, demonstrating the importance of replicating research across countries. Our findings should also be considered when formulating guidelines for future stay-at-home directives, enabling individuals to stay well despite the closure of public resources.