Introduction <p>Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) affects up to 9% of average-risk and 40% of high-risk patients. Rectal NSAIDs are guideline-recommended for PEP prophylaxis, yet direct evidence comparing different NSAIDs remains scarce. This study systematically evaluates head-to-head evidence to compare the efficacy of rectal diclofenac versus indomethacin in the prevention of PEP.</p> Methodology <p>This systematic review and meta-analysis adhered to the PRISMA guidelines and was prospectively registered in PROSPERO (CRD420251107055). Eligible studies directly compared rectal diclofenac versus indomethacin for PEP prevention in adults undergoing ERCP. A comprehensive search of five databases was performed through July 2025. Pooled risk ratios with 95% CIs were calculated using fixed- or random-effects models based on heterogeneity, and certainty of evidence was assessed using the GRADE approach.</p> Results <p>Four studies (three RCTs, one observational; n = 2,917) compared rectal diclofenac (n = 1,275) and indomethacin (n = 1,642) for PEP prevention. Baseline characteristics were comparable, except for less frequent balloon dilatation with diclofenac (RR 0.78, 95% CI 0.68–0.89; p &lt; 0.001). No significant differences were found for overall PEP (RR 1.17, 95% CI 0.92–1.49; I² = 0%), mild PEP (RR 1.24, 95% CI 0.94–1.63; I² = 0%), moderate PEP (RR 0.60, 95% CI 0.21–1.73; I² = 0%), severe PEP (RR 1.09, 95% CI 0.32–3.77; I² = 1%), or moderate-to-severe PEP (RR 0.97, 95% CI 0.46–2.05; I² = 0%). Secondary outcomes, including mortality and complications, were also similar, with low heterogeneity, indicating equivalent efficacy and safety.</p> Conclusion <p>Diclofenac and indomethacin demonstrate equivalent efficacy and safety, allowing cost and availability to inform the choice of PEP prophylaxis.</p>