The prevalence of obesity is growing rapidly worldwide, and therefore there is a need for effective treatment strategies. The rationale of combination therapy in treating chronic diseases, such as obesity, is the potential additive or synergistic effects. This review considers the results of phase III clinical trials with naltrexone sustained-release (SR) + bupropion SR combination therapy in obese patients with or without type 2 diabetes mellitus. We also discuss the potential therapeutic applications of this weight-reducing treatment option. Recent clinical trials have shown that the administration of naltrexone SR + bupropion SR resulted in effective weight loss. Furthermore, this treatment was associated with improvement in cardiometabolic variables. Depression and suicidal ideation were more frequently reported in the placebo compared with the combination groups. However, significantly more patients on naltrexone SR + bupropion SR experienced adverse events, mainly nausea, and discontinued treatment compared with placebo. Increases in blood pressure and pulse rate were observed only in the combination groups. Further investigation is needed to clarify the clinical significance of this weight-reducing therapeutic option.