It has been demonstrated that the KDM3 family of histone demethylases (KDM3A and KDM3B) epigenetically control the functional properties of colorectal cancer stem cells (CSCs) through Wnt/β-catenin signaling. Meanwhile, a broad-spectrum histone demethylase inhibitor, IOX1, suppresses Wnt-induced colorectal tumorigenesis predominantly through inhibiting the enzymatic activity of KDM3. In this work, several cereblon (CRBN)-recruiting PROTACs with various linker lengths were designed and synthesized using IOX1 as a warhead to target KDM3 proteins for degradation. Two of the synthesized PROTACs demonstrated favorable degradation profile and selectivity towards KDM3A and KDM3B. Compound 4 demonstrated favorable in vitro metabolic profile in liver enzymes as well as no hERG-associated cardiotoxicity. Compound 4 also showed dramatic ability in suppressing oncogenic Wnt signaling to eliminate colorectal CSCs and inhibit tumor growth, with around 10- to 35-fold increased potency over IOX1. In summary, this study suggests that PROTACs provide a unique molecular tool for the development of novel small molecules from the IOX1 skeleton for selective degradation of KDM3 to eliminate colorectal CSCs via suppressing oncogenic Wnt signaling.