Endoscopic retrograde cholangiopancreatography (ERCP) with transpapillary metal stenting is the standard palliation method for malignant distal biliary obstruction (MDBO); however, post-ERCP pancreatitis are not uncommon. Endoscopic ultrasonography-guided biliary drainage (EUS-BD) with transmural metal stenting has emerged as an option for primary palliation of MDBO. We compared the efficacy and safety of these procedures as first-line MDBO treatment. We searched for relevant English-language articles in PubMed, Embase, and Cochrane databases. The outcomes of interest were technical success, clinical success, adverse events, stent patency, reintervention rates, and procedure time. Subgroup analysis was performed for patients without duodenal invasion (eg, endoscopically accessible papilla; EUS-choledochoduodenostomy [CDS] vs. ERCP). Ten studies (3 randomized trials and 7 retrospective studies) with 756 patients were included. The cumulative technical and clinical success rates were high for both procedures (EUS-BD: 94.8% [294/310] and 93.8% [286/305], ERCP: 96.5% [386/400] and 95.7% [377/394]). The cumulative adverse event rates were 16.3% (54/331) for EUS-BD and 18.3% (78/425) for ERCP. In subgroup analysis for patients without duodenal invasion, EUS-CDS showed similar cumulative technical and clinical success rate with ERCP (technical success rate, EUS-CDS vs. ERCP: 94.2% [146/155] vs. 97.8% [237/242]; clinical success rate, EUS-CDS vs. ERCP: 94.2% [145/154] vs. 93.0% [225/242]). The cumulative rate of adverse events for EUS-CDS and ERCP was also comparable (15.5% [24/155] for EUS-CDS and 18.6% [45/242] for ERCP). As first-line palliation of MDBO, EUS-BD was similar to ERCP in technical and clinical success and safety; however, larger randomized trials comparing EUS-CDS and ERCP in this setting with endoscopically accessible papilla may be required.