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Despite widespread recognition that racial, class, gender, and sexual minorities are more vulnerable to adverse mental health, prior research has not fully clarified whether these disparities persist during a major public health crisis like the COVID-19 pandemic. Building on intersectionality theory and stress research, this study analyzes national survey data collected between April and June 2020, providing evidence on how race, class, gender, and sexual identities are associated with mental health outcomes during COVID-19. Findings indicate that while Blacks and Asians reported adverse mental health symptoms less frequently than Whites, females exhibited higher rates than males. Sexual minorities (LGB+) experienced adverse mental health more often than their straight counterparts. Lower- and middle-class individuals show greater susceptibility than upper-class respondents. Most importantly, the intersections of class, gender, and sexual identities amplify vulnerability significantly. This study contributes broadly to scholarship on the relationship between intersectionality and mental health and highlights the need for targeted public health interventions during public health emergencies such as COVID-19.