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Eligible criteria for an included trial were\u2009\u2264\u200924\u00a0weeks, randomized controlled trials (RCTs) that compared olanzapine\/samidorphan and olanzapine treatments in patients\/healthy volunteers and reported weight or cardiometabolic outcomes. Three databases were searched on October 31, 2020. Primary outcomes included weight changes and all-cause dropout rates. Standardized mean differences (SMDs) and risk ratios (RRs) were computed and pooled using a random-effect model. This meta-analysis included four RCTs (n\u2009=\u20091195). The heterogeneous data revealed that weight changes were not significantly different between olanzapine\/samidorphan and olanzapine groups (4 RCTs, SDM\u2009=\u2009\u2212\u00a00.19, 95% CI \u2212\u00a00.45 to 0.07, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u200975%). The whole-sample, pooled RR of all-cause dropout rates (4 RCTs, RR\u2009=\u20091.02, 95% CI 0.84 to 1.23, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u20090%) was not significant different between olanzapine\/samidorphan and olanzapine groups. A lower percentage of males and a lower initial body mass index were associated with the greater effect of samidorphan in preventing olanzapine-induced weight gain. Current evidence is insufficient to support the use of samidorphan to prevent olanzapine-induced weight gain and olanzapine-induced cardiometabolic abnormalities. 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