Background <p>Oxidative&#xa0;stress is an early step in the cascade of events triggering post-ERCP pancreatitis (PEP). N-acetylcysteine (NAC), a free radical scavenger, can be used to check this oxidative stress for PEP prophylaxis.&#xa0;</p> Methods <p>A systematic search of MEDLINE, EMBASE and Scopus was undertaken from inception to May 30,&#xa0;2025. The relative risks (RR) of PEP and severe PEP were pooled using a random effects model with the inverse variance method. Funnel plot and Egger’s test were used to evaluate publication bias. The quality of studies was assessed using the Cochrane risk of bias tool.&#xa0;</p> <p>Further sensitivity analysis was undertaken to evaluate oral route dosing and a leave-alone-one sensitivity analysis was done to confirm the robustness of the results (PROSPERO ID CRD420251062268).</p> Results <p>The five studies meeting the inclusion criteria included 784 participants of which 388 received NAC and 396 received placebo. PEP occurred in 50 participants in the NAC group as compared to 68 participants in the placebo group with a pooled RR of 0.74 (95% confidence interval [CI] 0.48 to 1.15) with moderate heterogeneity, I² 35%. Severe PEP occurred in none of the participants administered NAC as compared to three participants administered placebo with a pooled RR of 0.27 (95% CI of 0.03 to 2.43), with I² of 0% and no publication bias confirmed by no funnel plot visual asymmetry or Egger’s test (<i>p</i> = 0.220). Sensitivity analysis confirmed the robustness of the results.</p> Conclusion <p>The pooled results of the meta-analysis suggest that NAC prophylaxis does not prevent the occurrence of PEP or severe PEP as compared to placebo.</p> Graphical Abstract <p></p>