EUS-guided biliary drainage (EUS-BD) and percutaneous transhepatic cholangiography biliary drainage (PTC) are the two alternate methods for biliary decompression in cases where ERCP fails. We conducted a systematic review and meta-analysis of studies to compare the efficacy and safety of endoscopic and percutaneous biliary drainage for malignant biliary obstruction in patients with failed ERCP. A total of ten studies were included, fulfilling the inclusion criteria, including four retrospective studies and six randomized controlled trials. We compared the technical and clinical success rates and the acute, delayed, and total adverse events of EUS-BD with PTC. The odds ratios (ORs) and confidence intervals (CIs) were calculated. There was no difference between technical (OR: 0.47 [95% CI: 0.20–1.07]; P = 0.27) and clinical (OR: 2.24 [95% CI: 1.10–4.55]; P = 0.51) success rates between EUS-PD and PTC groups. Procedural adverse events (OR: 0.17 [95% CI: 0.09–0.31]; P = 0.03) and total adverse events (OR: 0.09 [95% CI: 0.02–0.38]; P < 0.01) were significantly different between the two groups; however, delayed adverse events were nonsignificantly different (OR: 0.73 [95% CI: 0.34–1.57]; P = 0.97). This meta-analysis indicates that endoscopic biliary drainage (EUS-BD) is equally effective but safer in terms of acute and total adverse events than percutaneous transhepatic biliary drainage (PTC) for biliary decompression in patients with malignant biliary strictures who have failed an ERCP.