Background and Aims EUS-guided biliary drainage (EUS-BD) has emerged as an alternative procedure after failed ERCP. However, limited data on the efficacy and safety of EUS-BD are available. Therefore, a systematic review was conducted to evaluate the efficacy and safety of EUS-BD and to evaluate transduodenal (TD) and transgastric (TG) approaches. Methods PubMed and EMBASE were searched to identify relevant studies published in the English language for inclusion in this systematic review and meta-analysis. Data from eligible studies were combined to calculate the cumulative technical success rate (TSR), functional success rate (FSR), and adverse-event rate of EUS-BD and the pooled odds ratio of TSR, FSR, and adverse-event rate of the TD approach when compared with the TG approach. Results Forty-two studies with 1192 patients were included in this study, and the cumulative TSR, FSR, and adverse-event rate were 94.71%, 91.66%, and 23.32%, respectively. The common adverse events associated with EUS-BD were bleeding (4.03%), bile leakage (4.03%), pneumoperitoneum (3.02%), stent migration (2.68%), cholangitis (2.43%), abdominal pain (1.51%), and peritonitis (1.26%). Ten studies were included in the meta-analysis for comparative evaluation of TD and TG approaches for EUS-BD. Compared with the TG approach, the pooled odds ratio of the TSR, FSR, and adverse-event rate of the TD approach were 1.36 (95% CI, .66-2.81; P > .05), .84 (95% CI, .50-1.42; P > .05), and .61 (95% CI, .36-1.03; P > .05), respectively, which indicated no significant difference in the TSR, FSR, and adverse-event rate between the 2 groups. Conclusions Although it is associated with significant morbidity, EUS-BD is an effective alternative procedure for relieving biliary obstruction. There was no significant difference between the TD and TG approaches for EUS-BD.