Background: Social support is a crucial factor in mitigating psychological distress among nursing students. However, the specific mechanism through which social support influences psychological distress, particularly the mediating role of school-life interference, remains underexplored. Aim The researchers investigated the relationship between social support and psychological distress in nursing students and examined the extent to which school-life interference mediates this relationship. Methods: A cross-sectional research design was employed. Data were collected from 1014 nursing students from three government universities in the Philippines. Three standardized scales were used: the Perceived Social Support Questionnaire (PSSQ), School-Life Interference Scale (SLIS), and the Perceived Stress Scale (PSS). Descriptive statistics, correlation analysis, and mediation analysis were conducted to analyze the data. Results: The findings revealed a moderate level of perceived social support (M = 3.554, SD = 0.775), high levels of school-life interference (M = 3.923, SD = 0.638), and significant psychological distress (M = 3.505, SD = 0.808). Social support was negatively associated with psychological distress ((3 = -0.1547, p < 0.001) and school-life interference ((3 = -0.0829, p = 0.001). School-life interference partially mediated the relationship between social support and psychological distress ((3 = -0.0375, LLCI = -0.0633 to ULCI = -0.0126). Conclusion: Social support played a crucial role in mitigating school-life interference, which subsequently reduced psychological distress among nursing students. Furthermore, the interventions aimed at enhancing social support and reducing school-life interference should be integrated into nursing education programs to support students' psychological well-being and academic success.