OBJECTIVE: Pain is a significant issue in post-hemorrhoidectomy. Metronidazole is being explored as an adjunctive pain management option. This meta-analysis of randomized controlled trials (RCTs) assesses metronidazole's effectiveness and safety compared to a placebo post-hemorrhoidectomy, aiming to provide evidence-based pain management guidance. METHOD: We conducted a systematic search of the Cochrane Library, Embase, PubMed, Web of Science, and ClinicalTrials.gov for RCTs comparing metronidazole to placebo after hemorrhoidectomy, covering the period from database inception to July 21, 2024. After screening per inclusion/exclusion criteria, study quality was assessed using Cochrane Handbook's risk of bias tool (version 5.1.0). The meta-analysis was conducted using RevMan 5.3 software, the quality of outcome indicators was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system, and trial sequential analysis (TSA) was employed to verify the adequacy of the sample size. RESULTS: A total of 9 RCTs were included. The meta-analysis results showed that the pain scores on the first day post-operation [MD=-1.07, 95% CI (-1.85, -0.30), P = 0.006], the second day post-operation [MD=-1.72, 95% CI (-2.62, -0.81), P = 0.0002], the seventh day post-operation [MD=-1.73, 95% CI (-2.70, -0.76), P = 0.0005], and the fourteenth day post-operation [MD=-1.80, 95% CI (-2.67, -0.94), P <
0.0002] in the metronidazole group were lower than those in the placebo group. Additionally, the rate of additional analgesia was reduced [RR = 0.48, 95% CI (0.27, 0.84), P = 0.01]. No statistically significant differences were found between the metronidazole and placebo groups in terms of the overall incidence of complications [RR = 0.69, 95% CI (0.41, 1.16), P = 0.16] and time to return to normal activities [MD=-1.69, 95% CI (-6.58, 3.20), P = 0.50]. Sensitivity analysis indicated that the results for pain scores on the first day post-operation were unstable. High heterogeneity was observed in pain scores on the first, second, seventh, and fourteenth days post-operation, as well as in the time to return to normal activities. The TSA indicated that the sample size for the primary outcome measures had achieved the required information size (RIS), supporting the strength and dependability of the meta-analysis findings. CONCLUSION: Metronidazole may be effective and safe in reducing postoperative pain in patients undergoing hemorrhoidectomy. However, due to the limitations of this study, further verification is needed from future large-sample, multi-center, well-designed high-quality RCTs. CLINICAL TRIAL NUMBER: Not applicable.