CONTEXT: This case report is interesting because it highlights a direction for the treatment of comorbid obesity and cocaine use disorder, which is an increasing clinical condition from an epidemiological point of view, and allows us to identify the possibility of a new strategy to address the problem of substance craving, particularly for cocaine. CASE PRESENTATION: This case report discusses the efficacy of semaglutide in a 54-year-old Caucasian patient with a history of cocaine abuse and obesity. Subcutaneous semaglutide was administered, as per guidelines, with a progressive weekly increase for a total of 12 weeks. The patient was monitored with respect to clinical parameters, as well as psychodiagnostic ones. The patient demonstrated significant weight loss and a marked reduction in cocaine craving. CONCLUSION: The action of semaglutide on the hunger and reward centers offers a new approach to the treatment of patients with obesity and concomitant substance use disorders. By targeting glucagon-like peptide-1 receptors involved in both metabolic regulation and reward processing, semaglutide could potentially reduce both food intake and drug craving, thereby improving outcomes for these patients. The findings suggest that semaglutide may be a promising therapeutic option for the management of substance abuse in patients with comorbid obesity.