In recent years, college students have experienced increased levels of stress accompanied by dramatic increases in anxiety and depression. Thus, it is important to understand what factors may be protective for late adolescents, specifically first-year college students. Cultural values have been shown to help alleviate stress while attending college. Furthermore, maintaining a consistent connection with family and home communities (i.e., social support) is critical for college students’ success. The current study investigates how stressful life events are associated with depressive symptoms, anxiety, and self-esteem and the role of familism and social support among diverse late adolescents attending their first year of college. Participants (N = 387, 75.6% female) were first-year undergraduate students who completed an online survey assessing stressful life events, depressive symptoms, anxiety, self-esteem, social support, and familism. Consistent with hypotheses, hierarchical multiple regression analyses revealed that stressful life events were positively associated with depressive symptoms and anxiety, and negatively associated with self-esteem. Surprisingly, familism support and social support did not moderate the effects of stress on mental health. A post-hoc was tested to examine the interaction between familism support and social support predicting mental health variables. Results revealed that participants who endorsed higher values of familism support, but reported lower perceived social support were more likely to experience greater depressive and anxiety symptoms. Familism and social support were found to be protective, but only when participants rated both highly, suggesting that both variables need to be present to moderate the effects of stress. Results illuminate the prevalence of stressful life events among college students and the detrimental effects of them.