Little is known about the impending mental health impacts of the global nature crisis. Existing evidence largely overlooks how nature sustains the economic and material dimensions of people’s lives that support their mental health. Moreover, this evidence poorly represents the context-dependent experiences of billions living in the rural Global South. Here, we offer a framework illustrating how nature’s essential contributions to people underpin multiple social determinants of mental health. We explore how the loss of those contributions (e.g., fisheries collapse) may exacerbate social determinants (e.g., poverty) of poor mental health. We examine how biodiversity conservation may affect mental health by altering the flow of nature’s contributions, regulating access to those contributions, generating direct impacts through projects, and tackling the underlying drivers of nature loss (illustrated empirically-based scenario analysis in Uganda). A better understanding can simultaneously guide policy and practice to tackle nature loss while protecting and enhancing mental health globally.