As the burden of mental health disorders continues to increase worldwide, there is significant need to describe the cultural variations in presentation, diagnosis and treatment of these diseases. An understanding of these variations can lead to the development of more effective programs to manage these conditions. In Guatemala, depression is the second-leading cause of disability and yet mental health treatment resources are scarce, particularly for indigenous individuals. The primary research aim was to describe primary care nurses' explanatory models of depression in their clinical work in indigenous communities in Guatemala. A secondary research aim was to describe training and resources which would support and empower these nurses, in order to lessen risk for burnout. A cross-sectional mixed methods survey was designed to elicit nurses' perspectives on the presentation, cause and treatment of depression in the communities they serve, as well as their clinical and emotional comfort in working with depressed individuals. Two subsequent focus groups gathered qualitative commentary which informed training and resource recommendations. Theoretical thematic analysis was used to generate codes and themes from focus group transcripts and survey responses. Guatemalan primary care nurses described symptoms of depression in their cultural context, identified socioeconomic factors which contribute to depression in their communities, and detailed treatment preferences. Limited referral options and concern for privacy made connecting patients to mental health care difficult. Nurses emphasized the need for community education on depression and for supplemental mental health resources which would increase their capacity to identify and treat depression. Primary care nurses in Guatemala identify and treat depression despite limited resources. Further investigations should focus on creating training modalities which include front-line nurses, given their critical role in the health system.