Background: Guidelines in the United States and Europe recommend the addition of olanzapine to the standard triple antiemetic therapy for chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC). However, no meta-analysis has directly compared the efficacy and safety of standard triple antiemetic therapy with the addition of olanzapine for CINV in patients only receiving HEC. This study aimed to conduct such a meta-analysis of randomized controlled trials. Methods: We searched the MEDLINE, Cochrane Library, and Igaku Chuo Zasshi databases for articles published between 1966 and October 2021 for randomized controlled trials (RCTs) that compared the efficacy and safety of the two therapies for CINV in patients receiving HEC. Results: Among the 1041 relevant articles, five RCTs were eligible for inclusion in the meta-analysis. The add-on olanzapine therapy was significantly more effective than the standard triple antiemetic therapy; the odds ratio [95% confidence interval] of complete response, no nausea, no vomiting, and the use of rescue medications were 2.30 [1.80 to 2.95], 1.84 [1.22 to 2.78], 2.71 [1.59 to 4.61], and 0.59 [0.48 to 0.74], respectively. The add-on olanzapine therapy was associated with mild somnolence more frequently than the standard triple therapy (2.20 [1.26 to 3.85]); however, it did not affect the treatment continuation. The incidence of insomnia was significantly low (0.72 [0.54 to 0.95]) with additional olanzapine therapy, and that of hyperglycemia was comparable between the two groups (2.33 [0.34 to 15.91]). Conclusions: The present meta-analysis would endorse that the add-on olanzapine therapy demonstrated significantly higher efficacy and tolerability than standard triple antiemetic therapy in CINV patients receiving HEC.