The lack of effective strategies remains a pivotal challenge for hepatocellular carcinoma (HCC) treatment. YAP/ TAZ is a promising target for effective drugs against HCC. In this study, we profiled the regulatory effect of 98 drugs on transcriptional activity of YAP/TAZ and identified the calcimimetic agent cinacalcet as a potent YAP inhibitor. Cinacalcet inhibited YAP expression in HCC models at both transcriptional and protein levels, and ultimately arrested cell proliferation of HCC. Overexpression of YAP weakened the anticancer efficacy of cinacalcet, indicating that YAP was responsible for the antineoplastic activity of cinacalcet. Collectively, this study suggested cinacalcet as a feasible anticancer drug for HCC via its inhibition on YAP/TAZ.