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Background: Olanzapine is an atypical antipsychotic drug used for chemotherapy-induced nausea and vomiting. It is particularly effective in preventing delayed nausea and vomiting induced by highly emetogenic chemotherapy (HEC). However, it has side effects, such as hyperglycemia and somnolence, the efficacy and safety of adding olanzapine to triplet antiemetic therapy (5-HT3 receptor antagonist, NK1 receptor antagonist, and dexamethasone) must be verified. Methods: We performed a systematic review and meta-analysis to compare the effectiveness of olanzapine combined with triplet antiemetic therapy and triplet antiemetic therapy in preventing nausea and vomiting for HEC. We set five items (hyperglycemia, prevention of vomiting, prevention of nausea, adverse events, and cost (drug costs)) as outcomes and conducted a systematic review. Results: Five randomized controlled trials was extracted and they showed that the addition of olanzapine was effective in control of nausea and vomiting, especially in the delayed phase. Complete response of acute and delayed phase were significantly higher in the olanzapine group. Risk difference was − 0.14 [95% CI − 0.26, − 0.03; p = 0.02] and − 0.14 [95% CI − 0.19, −0.09; p < 0.00001], respectively. Additionally, we evaluated hyperglycemia and somnolence, which are typical side effects of olanzapine. However, the incidence of grade ≥ 2 was low in both events, and there was no significant difference between olanzapine and control groups. Conclusions: Adding olanzapine to triplet antiemetic therapy is useful in preventing nausea and vomiting induced by HEC and there would be minimal adverse effects from the combination use. [ABSTRACT FROM AUTHOR]