Inhibition of the extracellular signal-regulated kinases 1/2 (ERK1/2) alone or in combination with other targets has emerged as a promising treatment strategy for a variety of human tumors. In addition to the development of inhibitors, the development of ERK1/2 degraders is an alternative approach to decrease its activity. We synthesized proteolysis-targeting chimeras (PROTACs) as effective ERK1/2 degraders, among which showed high degradative activity, with DC of 102 nM and cytotoxic IC of 2.2 μM against HCT116 cells. Moreover, dose-dependently inhibited tumor cell migration. Xenograft experiments in nude mice demonstrated that inhibited HCT116 tumor cell growth and achieved significant regression of tumors at a daily dose of 25 mg/kg.