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Abstract Background Patients undergoing Extracorporeal Membrane Oxygenation (ECMO) are particularly susceptible to infections: 42% experience sepsis and 26% develop a nosocomial infection (NI). Whether antibiotic prophylaxis is effective in reducing mortality and its effects on the rate of NIs is currently unclear. Research question Can antibiotic prophylaxis decrease 30-day mortality for patients on ECMO? Can antibiotic prophylaxis prevent the occurrence of NIs in these patients? Study design and methods A systematic review and meta-analysis was conducted. We searched PubMed, Scopus, and CINAHL libraries from inception to June 12, 2024. Two researchers were involved in abstract screening and three researchers were involved in full text selection. Results A pooled population of 7,996 patients is represented by 5 retrospective studies. Reported mortality ranges between 46 and 58% and the NIs rate is between 14 and 62%. Regarding 30-day mortality, the random-effects model (I2 = 65%) indicates a non-statistically significant difference between the antibiotic prophylaxis group and the non-prophylaxis group (OR 0.76; 95%CI 0.37–1.59). For the NIs rate, a fixed-effect model (I2 = 36%) shows an OR of 0.81 (95%CI 0.71–0.92) in favor of the antibiotic prophylaxis group, with a number-needed-to-treat (NNT) of 39.7 patients. Conclusion According to a very low degree of certainty, antibiotic prophylaxis appears to have no impact on the 30-day mortality rate of ECMO recipients. The risk of NIs seems to decrease with antibiotic prophylaxis, even though the NNT is high. Prospective high-quality studies that address these specific clinical questions are necessary. Clinical trial registration PROSPERO: International prospective register of systematic reviews, 2024, CRD42024567037.