BACKGROUND: Depression is closely linked to an imbalance in the autonomic nervous system (ANS). However, the role of this imbalance in mediating the effects of sleep deprivation (SD) and vagus nerve stimulation (VNS) on emotional well-being is not fully understood. METHODS: A population-based analysis was conducted to explore the relationship between sleep duration, depression scores, and heart rate variability (HRV). Additionally, the chronic SD mouse model was established to assess the impact of preventive transcutaneous auricular VNS (taVNS) on pathological and behavioral changes. RESULTS: Our study found a significant link between sleep duration, depression severity, and HRV. Shorter sleep duration was associated with higher depression scores and lower RMSSD (a measure of HRV). In our rat model, insufficient sleep consistently impaired HRV. This effect was mitigated by taVNS, accompanied by corresponding changes in levels of IL-1β and IL-6, astrocyte and microglia activation, and tail suspension times. CONCLUSIONS: Using VNS as a preventive treatment for depression-risk individuals with insufficient sleep shows promise. It not only broadens the potential applications of VNS but also sheds light on its mechanism-particularly its role in enhancing vagal nerve function and balancing the ANS, as evidenced by HRV measurements.