Extensive data from both in vitro and animal studies have demonstrated the potency of a deregulated activated Wnt pathway. Herein, we report the antitumor effects of already established novel Wnt pathway inhibitors-ethacrynic acid (EA) and Ciclopiroxolamine (CIC) on various cancer cell lines using the WST-8 assay. Our results demonstrate the significant cytotoxic potency of EA and CIC in vitro and display their strong efficacy on various tumor cells. Of particular interest, colon cancer was the most significantly affected by both drugs of all the tumor types tested in this study. This study provides a strategy for targeting Wnt-driven cancers and highlights those cancers that show a higher susceptibility to the cytotoxic effects of the Wnt inhibitors as potential candidates for further study.