This study examined the factorial structure of the construct core self-evaluations (CSE) and tested a mediational model of the relationship between CSE and life satisfaction in college students with disabilities. We conducted a quantitative descriptive design using exploratory and confirmatory factor analysis and multiple regression analysis. Participants included 97 college students with disabilities majoring in science and technology who received academic and career support services from an urban university on the east coast of the United States. The four CSE traits (self-esteem, self-efficacy, emotional stability, and locus of control) all loaded onto one higher-order CSE variable. Perceived stress, positive affect, and social support were found to completely mediate the relationship between CSE and life satisfaction. CSE was validated as a unidimensional construct in a sample of college students with disabilities. Higher levels of CSE were associated with better life satisfaction because students with high CSE were better at coping with stress, maintaining a positive mood, and building social support than students with low CSE, and this was associated with a higher satisfaction with life. Future research should explore the development of interventions to increase CSE in order to reduce stress, improve affect, and build social support to increase positive psychosocial outcomes such as life satisfaction in college students with disabilities.