This study assesses the actual magnitude and scope of the impacts of the COVID-19 mitigation measures at the individual level, with special interest in subjective well-being (SWB), its relevance and how these negative effects are making it difficult to comply with the physical distancing policies. This is a comparative prospective cohort study conducted in six Latin American cities (Bogotá, Buenos Aires, Guayaquil, Lima, Santo Domingo, and Santiago de Chile). A multivariate linear regression model was used to assess the impact of variables related to COVID-19 on SWB, using the life satisfaction variable. The linear regression model controlled for personality dimensions, demographic and socioeconomic characteristics, and city fixed effects. We found the greatest reduction in wellbeing associated with loss of work or income, with variations in personality type, and socioeconomic factors such as type of employment and marital status. Factors associated with social capital provide a significant level of SWB protection.