Objectives: Acculturative stress has been linked to psychological distress, but few studies have explored the moderating role of social constraints on this relationship. Social constraints are the perception that social networks are unsupportive to stressor-related discussions. In the present study, the relationship between acculturative stress and psychological distress in Hispanic/Latino and Asian immigrants and the moderating role of social constraints in this relationship were examined. Method: Participants were 306 college students (169 Hispanics/Latinos, 137 Asians; 33.9% first-generation immigrants, 66.1% second-generation immigrants) from two Texas universities. Results: Correlation results showed that acculturative stress and social constraints were significantly associated with higher levels of psychological distress in Hispanics/Latinos and Asians. In addition, regression results indicated a significant three-way interaction effect among acculturative stress, social constraints, and racial/ethnic groups. Social constraints were found to moderate the relationship between acculturative stress and psychological distress in Asians but not in Hispanics/Latinos. Significant association between acculturative stress and psychological distress was found in Asians with higher levels of social constraints but not in Asians with lower levels of social constraints. Conclusions: These findings suggested that the interaction effect of acculturative stress and social constraints on psychological distress may be subject to cultural influences, and social constraints may have differential roles in Hispanics/Latinos and Asians. Potential implications on the development of culturally adaptive interventions for different racial/ethnic minority groups were discussed.