Mood disorders, such as depression, anxiety, addiction, and bipolar disorder, represent significant public health concerns due to their prevalence and impact on quality of life. Tetraspanins, a family of membrane proteins characterized by four transmembrane domains, are emerging as key players in the pathophysiology of these disorders. This narrative review aims to synthesize current evidence regarding the role of tetraspanins in mood disorders, focusing on their potential mechanisms of action and therapeutic implications. The review explores the multifaceted roles of tetraspanins in cellular processes such as signal transduction, cell adhesion, and membrane organization. Evidence suggests that disruptions in tetraspanin-mediated functions could contribute to the neurobiological alterations observed in mood disorders. Specific tetraspanins, such as CD9, CD63, and CD81, have been implicated in neuroinflammatory processes, neurotransmitter regulation, and neural plasticity, all of which are crucial in mood disorders’ etiology. By summarizing current findings, this review identifies knowledge gaps and proposes future research directions. The potential for tetraspanins as therapeutic targets is also discussed, with an emphasis on developing novel treatments that address underlying pathophysiological mechanisms. This comprehensive review underscores the importance of understanding tetraspanins’ role in mood disorders, offering insights that may contribute to more effective interventions.