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Postoperative endophthalmitis is a devastating complication of cataract surgery. Intracameral moxifloxacin has emerged as a promising prophylactic strategy due to its broad-spectrum properties and pre-formulated preparations. However, a robust synthesis of evidence from randomized controlled trials (RCTs) is needed to confirm its efficacy and safety. A systematic review and meta-analysis were conducted using evidence from PubMed, Scopus, Web of Science, and CENTRAL, including RCTs published up to August 2025. The primary outcome was the incidence of endophthalmitis, while secondary outcomes included endothelial cell count (ECC) and central corneal thickness (CCT). We pooled outcomes using risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) using Stata (version 18). A total of six RCTs involving 4,438 patients were included. Overall, one RCT demonstrated a low risk of bias, three RCTs raised some concerns, and two RCTs were assessed as having a high risk of bias. Intracameral moxifloxacin significantly reduced the incidence of postoperative endophthalmitis compared to the control group ( = 5 RCTs, RR: 0.22, 95% CI [0.07, 0.77], = 0.02). A sensitivity analysis excluding studies with a high risk of bias demonstrated that the effect remained statistically significant ( = 3 RCTs, RR: 0.183, 95% CI 0.038, 0.874, = 0.03), with no evidence of heterogeneity ( = 0%, = 0.65). There was no significant difference between the moxifloxacin and control groups regarding postoperative changes in ECC ( = 3 RCTs, MD: 22.17, 95% CI [-8.53, 52.88], = 0.16) or CCT ( = 3 RCTs, MD: -0.03, 95% CI [-0.36, 0.31], = 0.88). Prophylactic intracameral moxifloxacin significantly reduces the incidence of postoperative endophthalmitis following cataract surgery. This substantial protective benefit is achieved without evidence of compromised endothelial safety; however, safety conclusions are limited by the small number of patients assessed and should be interpreted with caution. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (ID: CRD420251144067), https://www.crd.york.ac.uk/PROSPERO/view/CRD420251144067.