Purpose Palonosetron, a second-generation 5-hydroxytryptamine 3 receptor antagonist (5-HT(3)RA), has unique characteristics relative to first-generation 5-HT3RAs such as ondansetron. Nevertheless, it remains unclear if palonosetron is better than ondansetron for the prevention of nausea and vomiting during the first 24 hr after surgery and is thus the focus of this systematic review. Methods We conducted a systematic search of the MEDLINE (R), EMBASE (TM), Cochrane Central Register of Controlled Trials and Web of Science (R) databases to identify randomized controlled trials (RCTs) that addressed a comparison of the prophylactic antiemetic efficacy between palonosetron and ondansetron within 24 hr after surgery. The primary outcomes were the proportion of participants who experienced postoperative nausea (PON), postoperative vomiting (POV), or both, in the early (0-6 hr) or late (6-24 hr) period. The pooled relative risks (RRs) were calculated along with their corresponding 95% confidence intervals (CIs). Results We identified nine RCTs that comprised 741 participants. Palonosetron was superior to ondansetron in the reduction of early PON [RR, 0.51; 95% CI, 0.37 to 0.71], late PON (RR, 0.53; 95% CI, 0.36 to 0.77), and late POV (RR, 0.41; 95% CI, 0.28 to 0.62), but not early POV (RR, 0.77; 95% CI, 0.45 to 1.34). Conclusion Palonosetron provides more effective prophylaxis of early PON, late PON, and late POV compared with ondansetron. Future studies are required to investigate the role of palonosetron during 24-72 hr following surgery.