It has recently been reported that a large proportion of human malignant pleural mesothelioma (MPM) cell lines and patient tissue samples present high expression of the c‐MYC oncogene. This gene drives several tumorigenic processes and is overexpressed in many cancers. Although c‐MYC is a strategic target to restrain cancer processes, no drugs acting as c‐MYC inhibitors are available. The novel thienotriazolodiazepine small‐molecule bromodomain inhibitor OTX015/MK‐8628 has shown potent antiproliferative activity accompanied by c‐MYC downregulation in several tumor types. This study was designed to evaluate the growth inhibitory effect of OTX015 on patient‐derived MPM473, MPM487 and MPM60 mesothelioma cell lines and its antitumor activity in three patient‐derived xenograft models, MPM473, MPM487 and MPM484, comparing it with cisplatin, gemcitabine and pemetrexed, three agents which are currently used to treat MPM in the clinic. OTX015 caused a significant delay in cell growth both in vitro and in vivo. It was the most effective drug in MPM473 xenografts and showed a similar level of activity as the most efficient treatment in the other two MPM models (gemcitabine in MPM487 and cisplatin in MPM484). In vitro studies showed that OTX015 downregulated c‐MYC protein levels in both MPM473 and MPM487 cell lines. Our findings represent the first evidence of promising therapeutic activity of OTX015 in mesothelioma. What's new? A large proportion of human malignant pleural mesothelioma (MPM) cell lines and patient tissue samples present high expression of the c‐MYC oncogene. While no drugs acting as c‐MYC inhibitors are available to date, the novel BET inhibitor OTX015/MK‐8628 has shown potent antiproliferative activity accompanied by c‐MYC downregulation in several tumor types. Here, the authors present the first evidence of antitumor activity of OTX015 in three novel patient‐derived MPM xenograft models, all showing significant delays in tumor growth. Downregulated c‐MYC protein levels were observed following OTX015 in vitro exposure. OTX015 may thus represent a promising therapeutic approach for MPM.