Substance use disorders, including stimulant use disorder (StUD) and cannabis use disorder (CUD), represent a major clinical challenge due to their chronic, relapsing course and the lack of approved pharmacotherapies for many of these conditions. Contemporary neurobiological models conceptualize addiction as a disorder of brain function, involving dysregulation of reward, stress, and executive control systems, thereby creating a rationale for treatments targeting specific neurofunctional domains. Bupropion, an antidepressant with a dual norepinephrine and dopamine reuptake inhibition (NDRI) mechanism, exerts effects consistent with these models by modulating key neural circuits involved in motivation, craving, and self-control. The aim of this paper is to review the neurobiological rationale and available clinical evidence supporting the use of bupropion in the treatment of StUD and CUD. The drug’s mechanism of action is discussed in the context of the three-stage addiction cycle, along with findings from clinical and pilot studies evaluating its efficacy in reducing withdrawal symptoms, craving, and substance use. Attention is given to current clinical recommendations and the safety profile of bupropion. Available evidence suggests that bupropion may represent a valuable component of integrated, individualized treatment approaches for StUD and CUD, especially in patients with specific clinical profiles and comorbidities. However, further high-powered randomized controlled trials are needed to more precisely define its role in the treatment of these disorders.