Colon cancer is a commonly diagnosed cancer that often has a poor prognosis. Combined with the development of drug resistance to cancer treatment agents the treatment efficacy of colon cancer can be limited. Activation of the oncogene YAP has been shown to be related to colon cancer progression and is associated with poor prognosis, drug resistance and metastasis, even under treatment. Cisplatin (DDP) is a commonly used drug that can control carcinoma progression, although its mechanisms are poorly understood. In the present study, we examined whether DDP specifically suppressed YAP in order to inhibit colon carcinoma progression. Our data revealed that Mst/Yap signaling was unusually activated in colon cancers, promoting cell proliferation and invasion. DDP treatment decreased the expression of YAP at both the transcriptional and post-translational levels, leading to cell cycle arrest, apoptosis and senescence in cancer cells, in addition to decreasing epithelial-to-mesenchymal transition, cell motility and in vitro cell invasion and migration. Ultimately, DDP increased the expression of E-cadherin and decreased the expression of vimentin. The present study also revealed that post-translational regulation of YAP phosphorylation controlled the subcellular distribution between the nucleus and the cytoplasm. In conclusion, the findings of the present study revealed that DDP was a suitable therapeutic candidate for colon cancer that specifically targets the Mst/Yap signaling pathway.