Background: although diarrheal diseases are preventable and treatable, they are the leading cause of child mortality and morbidity as a consequence of poor hygiene and contaminated water. Handwashing with soap is an effective method for preventing and decreasing the incidence of diarrhea. However, mental disorders such as depression can substantially moderate an individual's ability to cope with daily life and can exert a negative influence on daily hygiene activities such as handwashing with soap, especially in children. The aim of this study was to explain the influence of depression on pupils' hand-washing behavior in Zimbabwe. Methods: in a cross-sectional study, face-to-face interviews were carried out with primary school pupils in peri-urban Harare, Zimbabwe (n = 556) using a quantitative questionnaire to assess handwashing and its behavioral determinants in school settings. The Center for Epidemiological Studies Depression Scale for Children (CES-DC) was used to assess depression. Results: more than half of the assessed children were depressed. Self-reported handwashing with soap among depressed children was significantly lower than among non-depressed children. Almost all behavioral determinants of hand-washing behavior were significantly lower in depressed children. The behavioral determinants worked differently in the depressed children than in the non-depressed children's group. The effects of important behavioral determinants on handwashing were moderated by depression. Conclusions: depression exerts a negative influence on handwashing in children. These results suggest depression-relieving measures should be conducted together with any water, sanitation, and hygiene (WASH) interventions to make such interventions more effective.