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Abstract Background This study investigated whether combination therapy with vasopressin, steroid, and epinephrine (VSE) improves in-hospital survival and return of spontaneous circulation (ROSC) during and after resuscitation in-hospital cardiac arrest (CA). Materials and methods Various databases were explored from inception until October 2021 for relevant published clinical trials and cohort studies. Results Three clinical trials were included. Pooled analysis suggested that VSE was significantly associated with increased ROSC in patients with in-hospital CA (IHCA) (odds ratio (OR): 2.281, 95% confidence interval (CI): 1.304–3.989, P value = 0.004). Meta-analysis of two studies (368 patients) demonstrated a significant difference in the reduction of mean arterial pressure (MAP) during and 15–20 min after cardiopulmonary resuscitation (standardized mean difference (SMD): 1.069, 95% CI: 0.851–1.288, P value < 0.001), renal failure free days (SMD = 0.590; 95% CI: 0.312–0.869 days; P value < 0.001), and coagulation failure free days (SMD = 0.403; 95% CI: 0.128–0.679, P value = 0.004). However, no significant difference was observed for survival-to-discharge ratio (OR: 2.082, 95% CI: 0.638–6.796, P value = 0.225) and ventilator free days (SMD = 0.201, 95% CI: − 0.677, 1.079 days; P value = 0.838). Conclusions VSE combination therapy during and after IHCA may have beneficial effects in terms of the ROSC, renal and circulatory failure free days, and MAP. Prospero registration: CRD42020178297 (05/07/2020).