Endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) by bilateral or unilateral approach is widely used in palliative abdominal pain management in pancreatic cancer patients, but the analgesic effect and relative risks of the two different puncture routes remain controversial. The aim of this systematic review was to evaluate the analgesic efficacy and safety of bilateral EUS-CPN compared with unilateral EUS-CPN. An electronic database search was performed for randomized controlled trials comparing bilateral and unilateral approaches of EUS-CPN using the Pubmed, Cochrane Library, Web of Science, Google Scholar, and CNKI databases. Meta-analysis was performed using RevMan 5.3 after screening and methodological evaluation of the selected studies. Outcomes included pain relief, treatment response, analgesic reduction, complications, and quality of life (QOL). Six eligible studies involving 437 patients were included. No significant difference was found in short-term pain relief [SMD = 0.31, 95% CI (- 0.20, 0.81), P = 0.23] and response to treatment [RR = 0.99, 95% CI (0.77, 1.41), P = 0.97] between the bilateral and unilateral neurolysis groups. However, only the bilateral approach was associated with a statistically significant reduction in the postoperative use of analgesics [RR = 0.66, 95% CI (0.47, 0.94), P = 0.02] compared to the unilateral approach. A descriptive analysis was performed for complications and QOL. The short-term analgesic effect and general risk of bilateral EUS-CPN are comparable with those of unilateral EUS-CPN, but our evidence supports the conclusion that the bilateral approach significantly reduces postoperative analgesic use.