Percutaneous liver biopsy (PC-LB) has long been the usual method for acquisition of liver tissue. Recently, endoscopic ultrasound-guided liver biopsy (EUS-LB) has gained popularity as an alternative modality. We aimed to compare the efficacy and safety of EUS-LB versus PC-LB. We systematically searched PubMed, Embase, and the Cochrane Library databases for randomized controlled trials (RCTs) comparing EUS-LB with PC-LB published until October 20, 2023. The primary outcome was diagnostic adequacy. Secondary outcomes were: the number of complete portal tracts (CPTs), longest sample length (LSL), total sample length (TSL), post-procedure pain scores, and adverse events (AEs), including overall AEs and AEs excluding minor post-procedure symptoms. We compared binary outcomes using risk ratios (RRs) and continuous outcomes using the mean difference (MD) or standardized mean difference (SMD), with 95%CIs. Four RCTs (258 patients) were included. The EUS-LB group presented lower post-procedure pain scores (SMD -0.58, 95%CI -0.95 to -0.22) than the PC-LB group. Both groups performed similarly in terms of diagnostic adequacy (RR 1.0, 95%CI 0.96 to 1.04), number of CPTs (MD 2.57, 95%CI -4.09 to 9.22), LSL (MD -2.91 mm, 95%CI -5.86 to 0.03), TSL (MD 4.16 mm, 95%CI -10.12 to 18.45), overall AEs (RR 0.54, 95%CI 0.20 to 1.46), and AEs excluding minor post-procedure symptoms (RR 1.65, 95%CI 0.21 to 13.02). This meta-analysis suggests that EUS-LB is as safe and effective as PC-LB and is associated with lower post-procedure pain scores.Registration on PROSPERO: CRD42023469469.