Hispanic/Latinx student enrollment in U.S. colleges has increased over the last decade; however, disparities in degree completion still exist. Hispanic/Latinx college students experience a variety of challenges, including cultural stressors, that when compounded with stressors associated with the COVID-19 pandemic, further increase the risk for academic and mental health problems. Familismo and self-efficacy are protective factors for Hispanic/Latinx student mental health; yet their main and interaction effects in unique adverse circumstances, such as a global pandemic, are not yet well understood. Using survey data from a sample of Hispanic/Latinx college students, this study examined the impact of familismo, self-efficacy, and their interaction on mental health during the ongoing COVID-19 pandemic. Although results suggest that the main effects of familismo and self-efficacy are associated with fewer days during which students experienced mental health symptoms, the interaction between familismo and self-efficacy was associated with more days during which mental health symptoms were experienced. Study findings have implications for the development and implementation of culturally sensitive and responsive mental health and educational services for Hispanic/Latinx college students.