Objective To systematically evaluate the efficacy and safety of palonosetron hydrochloride injection for the prevention of chemotherapy-induced nausea and vomiting (CINV) associated with moderately or highly emetogenic chemotherapy. Methods Searched PubMed, Embase, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biological Medical Database, Wanfang Database and VIP Chinese Science and Technology Journal Database to find domestic and abroad published literatures of palonosetron used to control CINV associated with moderately or highly emetogenic chemotherapy. Two reviewers independently selected literatures, extracted data and assessed quality of the included studies by the Cochrane handbook 5.1. Meta-analysis was performed using RevMan 5.3 software. Results Twenty trials involving 4 919 patients were included. The results of meta-analysis showed statistically significant differences between palonosetron and first-generation 5-hydroxytryptamine3 receptor antagonists (5-HT3RAS) in prevention of acute〔RR=1.09, 95%CI (1.40, 1.14),P=0.000 4〕, delayed 〔RR=1.26, 95%CI (1.15, 1.37),P＜0.000 01〕, and overall phase of CINV 〔RR=1.19, 95%CI (1.10, 1.30),P＜0.000 1〕. Subgroup analyses indicated that there were no statistical significances between palonosetron and granisetron (P=0.09) or ondansetron (P=0.08) in prevention of acute CINV, as well as between palonosetron and first-generation 5-HT3RAS in prophylaxis of moderately CINV (P=0.18), while there was statistical significance in favor of palonosetron in prophylaxis of delayed and overall phase of CINV. Compared with first-generation 5-HT3RAS, there were different in prophylaxis of highly chemotherapy-induced acute〔RR=1.10, 95%CI (1.02, 1.18),P=0.01〕, delayed〔RR=1.20, 95%CI (1.06, 1.36),P=0.005〕, and overall phase〔RR=1.18, 95%CI (1.04,1.33),P=0.008〕of CINV. In terms of safety, such as headache, constipation, diarrhea and dizziness, there were no statistical differences between two groups. Conclusions Palonosetron hydrochloride injection showed efficacy in prophylaxis of moderately or highly CINV, and didn't increase adverse events. Palonosetron hydrochloride injection is more better than first-generation 5-HT3RAS, especially in prevention of highly CINV, and can significantly improve the control rate of acute, delayed, and overall phase of CINV.