Introduction: The vagus nerve has an important role in satiety, metabolism, and autonomic control in upper gastrointestinal function. However, the role and effects of vagal nerve therapy on weight loss remain controversial. This systematic review and meta-analysis assessed the effects of vagal nerve therapy on weight loss, body mass index (BMI), and obesity-related conditions. Methods: MEDLINE, EMBASE, and CINAHL databases were searched for studies up to April 2022 that reported on percentage excess weight loss (%EWL) or BMI at 12 months or remission of obesity-related conditions following vagal nerve therapy from January 2000 to April 2022. Weighted mean difference (WMD) was calculated, meta-analysis was performed using random-effects models, and between-study heterogeneity was assessed. Results: Fifteen studies, of which nine were randomised controlled trials, of 1,447 patients were included. Vagal nerve therapy led to some improvement in %EWL (WMD 17.19%; 95% confidence interval [CI]: 10.94–23.44; p < 0.001) and BMI (WMD −2.24 kg/m2; 95% CI: −4.07 to −0.42; p = 0.016). There was a general improvement found in HbA1c following vagal nerve therapy when compared to no treatment given. No major complications were reported. Conclusions: Vagal nerve therapy can safely result in a mild-to-moderate improvement in weight loss. However, further clinical trials are required to confirm these results and investigate the possibility of the long-term benefit of vagal nerve therapy as a dual therapy combined with standard surgical bariatric interventions.