Management of acute bronchiolitis remains controversial due to lack of strong evidence-based data. Nebulized epinephrine and hypertonic saline have been studied in infants with bronchiolitis, with conflicting results. This systematic review and meta-analysis aimed to evaluate the efficacy on length of stay (LOS), clinical severity scores (CSS), oxygen saturation (SaO2) and safety profile of nebulized epinephrine plus hypertonic saline (HS) in infants with acute bronchiolitis. Outcomes were represented by mean differences (MD) or standard mean differences (SMD) and 95% confidence intervals (CIs) were utilized. 18 trials were systematically selected and 16 of them contributed for the meta-analysis (1,756 patients). Overall, a modest but significant positive impact was observed of the combination therapy on LOS (MD of – 0.35 days, 95% CI -0.62 to -0.08, p = 0.01, I2 = 91%). Stratification by time of CSS assessment unveiled positive results in favor of the combination therapy in CSS assessed 48 hours and 72 hours after the admission (SMD of -0.35, 95% CI -0.62 to -0.09, p = 0.008, I2 = 41% and SMD of -0.27, 95% CI -0.50 to -0.04, p = 0.02, I2 = 0%, respectively). No difference in SaO2 was observed. Additional data showed a consistent safety profile, with a low rate of adverse events (1%), most of them mild and transient. In conclusion, nebulized epinephrine plus HS may be considered as a safe, cheap and efficient alternative for decreasing LOS and CSS in infants with acute bronchiolitis, especially on those who require more than 48 hours of hospitalization.