Poor prognoses for colorectal cancer (CRC) patients with metastatic lesions have driven demand for the development of novel targeted therapies. Here we demonstrate that expression of bone morphogenetic protein 4 (BMP-4) is universally upregulated in human CRC cells and tissues, resulting in activated BMP signaling. Inhibition of endogenous BMP signaling by the BMP type I receptor inhibitor LDN-193189 elevated expression of the phosphatase DUSP5 in CRC cells, inducing apoptosis via dephosphorylation of Erk MAPK. Administering LDN-193189 to mice diminished tumor formation of CRC cells. Our findings suggest inhibition of autocrine BMP-4 as a candidate treatment strategy for CRC.