This research paper explores the intricate interplay between mental health (MH), quality of life (QOL), religiosity, and social connectedness among students with disabilities. In the context of a growing awareness of the multifaceted nature of well-being, this study aims to unravel the moderating effects of religiosity and social connectedness on the relationship between mental health and the overall quality of life experienced by students with disabilities. Utilizing Partial Least Squares Structural Equation Modeling (PLS-SEM), this research investigates direct and moderating effects within the proposed conceptual framework. The results indicate that all mental health disorder dimensions (stress, depression, and anxiety) negatively and significantly affect the quality of life of students with disabilities; moreover, the negative impact of stress on QOL is dampened by the moderation effect of social connectedness. Similarly, the negative impact of anxiety on QOL is dampened by the moderation effect of religiosity. However, the findings indicate that social connectedness fails to dampen the negative impact of depression (and anxiety (β = −0.12)) on QOL. Similarly, the findings reveal that religiosity is unable to dampen the negative effect of depression and stress on QOL. These findings’ implications extend to the theoretical and practical domains, informing interventions and support systems aimed at enhancing the overall quality of life of people with disabilities.