Purpose <p>Most children with acute appendicitis are treated with laparoscopic appendectomy followed by antibiotics if the appendix is found to be perforated. There is variation in the type of post-operative antibiotics used for these patients.</p> Methods <p>We conducted systematic searches of Medline, Embase, and Cochrane for comparative studies of children with perforated appendicitis treated with post-operative piperacillin/tazobactam versus ceftriaxone and metronidazole.</p> Results <p>We identified four studies consisting of 25,730 children with perforated appendicitis treated with laparoscopic appendectomy followed by post-operative piperacillin/tazobactam (<i>n</i> = 9,950) or ceftriaxone and metronidazole (<i>n</i> = 15,780). One study was a randomized controlled trial (RCT) and three were multicenter observational studies. Meta-analysis suggested no differences between piperacillin/tazobactam and ceftriaxone and metronidazole in terms of deep/organ-space surgical site infection (risk ratio [RR] = 0.97, 95% confidence interval [CI] 0.57–1.65), post-operative imaging (RR = 0.99, 95% CI 0.71–1.37), return to the emergency department (RR = 0.82, 95% CI 0.50–1.37), and readmission to hospital (RR = 0.85, 95% CI 0.45–1.62). Heterogeneity between studies was substantial (I² 73–83%). The RCT was limited by possible ascertainment bias, while the three observational studies may have been affected by baseline differences between treatment groups.</p> Conclusion <p>This systematic review suggests that there is ongoing uncertainty regarding the optimal post-operative antibiotics for children with perforated appendicitis.</p> Clinical trial registration <p><a href="https://www.crd.york.ac.uk/PROSPERO/view/CRD42023421492">https://www.crd.york.ac.uk/PROSPERO/view/CRD42023421492</a>.</p>