Objectives: The current study investigates the utility of political activism as a protective factor against experiences of racial/ethnic (R/E) discrimination that negatively affect stress, anxiety, and depressive symptoms among Black and Latinx college freshmen at predominately White institutions. Method: Data come from the Minority College Cohort Study, a longitudinal investigation of Black and Latinx college students (N = 504; 44% Black). We conducted multiple regression analyses for each mental health indicator and tested for interaction effects. Results: For Black and Latinx students, the relationship between R/E microaggressions and end of freshman year stress varied by political activism. For Black students, the relationship between R/E microaggressions and end of the year anxiety varied by political activism. There was a significant interaction effect for depressive symptoms among Latinx students. Conclusions: Political activism serves as a protective factor to mitigate the negative effect of R/E discrimination on stress and depressive symptoms for Latinx students. For Black students, higher levels of political activism may exacerbate experiences of R/E microaggressions and relate to more stress and anxiety compared with Black students who are less politically involved. Findings point to the need for a deeper understanding of phenomenological variation in experiences of microaggressions among R/E minorities and how students leverage political activism as an adaptive coping strategy to mitigate race-related stress during college.