The current study investigates the effects of a multidisciplinary lifestyle intervention for obesity on Health Related Quality of Life (HRQoL). In this study, 92 adults with obesity were weighed and completed the Short Form Health Survey (SF-36) and the Center for Epidemiologic Studies Depression Scale (CES-D) at the baseline and at the end of a 3-month intervention. Repeated measures analysis of variance (ANOVA), a series of hierarchical regressions, and the statistical mediation analysis of Baron and Kenny were conducted. (a) Over 3 months, changes in weight and the mental and physical scales of the SF-36 and depression were all significant. (b) The results indicate a significant mediation of changes in depression scores for the association between weight loss and enhancement on the General Health scale of the SF-36. Improvements to HRQoL from a multidisciplinary lifestyle intervention seem to affect both the physical and mental components of the SF-36 score and to reduce depression, contributing to enhanced self-perceptions of well-being.