Previous studies of college entrance and graduation have identified strong ethnic identity, cultural congruity, and low acculturative stress as protective factors for academic persistence among Latina/o college students. However, lacking in the literature is a more differentiated and complete understanding of the complex relationships between cultural and psychosocial factors that may lead to college success for students attending Hispanic-Serving Institutions (HSIs) of higher education. Proposing a structural equation model, we examined positive effects of ethnic identity, cultural congruity, and low acculturative stress on emotional wellbeing and GPA of Latina/o students attending HSIs. Further, we explored whether sense of belonging and academic self-efficacy mediate the relationships between the aforementioned cultural factors and emotional wellbeing and GPA. Participants were 289 Latina/o college students attending a Hispanic-Serving Institution in a Southwest city. Results showed that cultural factors, including low acculturative stress and strong ethnic identity, had significant positive effects on emotional wellbeing and GPA. However, the effects of cultural congruity were not substantiated. The mediating effects of sense of belonging and academic self-efficacy on cultural factors and college success outcomes were partially supported. Implications for improving adjustment among Latina/o college students attending Hispanic-Serving Institutions are discussed.