Depression is the most common comorbidity and neuropsychiatric complication in HIV. Estimates suggest that the prevalence rate for depression among HIV-infected individuals is three times that of the general population. The association between HIV and clinical depression is complex; however, chronic activation of inflammatory mechanisms, which disrupt central nervous system (CNS) function, may contribute to this association. Disruptions in CNS function can result in cognitive disorders, social withdrawal, fatigue, apathy, psychomotor impairment, and sleep disturbances, which are common manifestations in depression and HIV alike. Interestingly, the parasympathetic system-associated vagus nerve (VN) has primary homeostatic properties that restore CNS function following a stress or inflammatory response. Unfortunately, about 30% of adults with HIV are resistant to standard psychotherapeutic and psychopharmacological treatments for depression, thus suggesting the need for alternative treatment approaches. VN stimulation (VNS) and its benefits as a treatment for depression have been well documented, but remain unexplored in the HIV population. Historically, VNS has been delivered using a surgically implanted device; however, transcutanous VNS (tVNS) with nonsurgical auricular technology is now available. Although it currently lacks Food and Drug Administration approval in the US, evidence suggests several advantages of tVNS, including a reduced side-effect profile when compared to standard treatments and comparable results to implantable VNS in treating depression. Therefore, tVNS could offer an alternative for managing depression in HIV via regulating CNS function; moreover, tVNS may be useful for treatment of other symptoms common in HIV. From this, implications for nursing research and practice are provided.