<jats:title>Abstract</jats:title><jats:p>Malignant mesothelioma (MM) is one of the most aggressive tumors. We conducted bioinformatics analysis using Cancer Cell Line Encyclopedia (CCLE) datasets to identify new molecular markers in MM. Overexpression of oxytocin receptor (<jats:italic>OXTR</jats:italic>), which is a G‐protein–coupled receptor for the hormone and neurotransmitter oxytocin, mRNA was distinctively identified in MM cell lines. Therefore, we assessed the role of <jats:italic>OXTR</jats:italic> and its clinical relevance in MM. Kaplan‐Meier and Cox regression analyses were applied to assess the association between overall survival and <jats:italic>OXTR</jats:italic> mRNA expression using The Cancer Genome Atlas (TCGA) datasets. The function of <jats:italic>OXTR</jats:italic> and the efficacy of its antagonists were investigated in vitro and in vivo using MM cell lines. Consistent with the findings from CCLE datasets analysis, <jats:italic>OXTR</jats:italic> mRNA expression was highly increased in MM tissues compared with other cancer types in the TCGA datasets, and MM cases with high <jats:italic>OXTR</jats:italic> expression showed poor overall survival. Moreover, <jats:italic>OXTR</jats:italic> knockdown dramatically decreased MM cell proliferation in cells with high <jats:italic>OXTR</jats:italic> expression via tumor cell cycle disturbance, whereas oxytocin treatment significantly increased MM cell growth. <jats:italic>OXTR</jats:italic> antagonists, which have high selectivity for OXTR, inhibited the growth of MM cell lines with high <jats:italic>OXTR</jats:italic> expression, and oral administration of the <jats:italic>OXTR</jats:italic> antagonist, cligosiban, significantly suppressed MM tumor progression in a xenograft model. Our findings suggest that <jats:italic>OXTR</jats:italic> plays a crucial role in MM cell proliferation and is a promising therapeutic target that may broaden potential therapeutic options and could be a prognostic biomarker of MM.</jats:p>