For many students with disabilities, the transition from high school to a postsecondary educational institution can be challenging as they navigate a new environment with new or different supports. Recent research has demonstrated strong relationships between core self-evaluations (CSE) and a variety of psychosocial and employment outcomes in individuals with disabilities. The purpose of this study was to test a mediation model of the relationship between CSE and life satisfaction in 195 college students with disabilities. Hayes’ (2018) PROCESS macro for SPSS was used to evaluate the model. The results showed that acceptance of disability, social support from significant others, employment-related self-efficacy, and social self-efficacy partially mediated the relationship between CSE and life satisfaction. The direct effect of CSE on life satisfaction was still significant after controlling for the effects of all mediators. Overall, CSE affected life satisfaction in college students with disabilities, both directly and indirectly, through improved disability acceptance, greater support from significant others, increased employment-related self-efficacy, and improved social self-efficacy. Implications of the results to improve life satisfaction in college students with disabilities are discussed.