A substantial portion of drug abuse research has concentrated on people with a single-substance-use disorder (SSUD), but many people abuse more than one drug. Studies have yet to examine how those with polysubstance-use disorder (PSUD) differ from those with an SSUD on the risk of relapse, self-evaluative emotions (e.g., shame and guilt), and personality factors (e.g., self-efficacy). Eleven rehab facilities in Lahore city, Pakistan were randomly chosen to provide a sample of 402 males with PSUD. For comparison, 410 age-matched males with SSUD were enlisted using a demographic form with eight questions, the State Shame and Guilt Scale, and the General Self-Efficacy Scale. Mediated moderation analysis was performed using Hayes’ process macro. The results demonstrate that shame-proneness is positively associated with relapse rate. Guilt-proneness mediates the relationship between shame-proneness and relapse rate. Self-efficacy buffers the influence of shame-proneness on relapse rate. Although the mediation and moderation effects were found in both study groups, these effects were significantly stronger among people with PSUD than those with SSUD. To be more specific, people with PSUD reported a higher overall score on shame, guilt, and relapse rate. Additionally, people with SSUD indicated a higher score on self-efficacy than those with PSUD. The findings of this study suggest that drug rehab facilities should implement a variety of strategies to raise drug users’ levels of self-efficacy, which will help to reduce their risk of relapse.