KRAS-PDEδ protein-protein interaction represents an appealing target for cancer therapy. However, fast release of high-affinity inhibitors from PDEδ hampered drug binding affinity and antiproliferative activity. To overcome the limitations, the first proteolysis-targeting chimeric (PROTAC) small molecules targeting PDEδ were designed. By employment of PDEδ inhibitor deltazinone (<b>2</b>) and cereblon ligand pomalidomide (<b>6</b>), a series of potent PROTAC PDEδ degraders were obtained. The most promising compound <b>17f</b> efficiently induced PDEδ degradation and demonstrated significantly improved antiproliferative potency in KRAS mutant SW480 cells. Compound <b>17f</b> also achieved significant tumor growth inhibition in the SW480 colorectal cancer xenograft model. This proof-of-concept study provided a new strategy to validate the druggability of KRAS-PDEδ interaction and offered an effective lead compound for the treatment of KRAS mutant cancer.