Structure-based design and optimization were performed to develop small-molecule β-catenin/B-cell lymphoma 9 (BCL9) inhibitors and improve their inhibitory activities. Compound ZL3138 with a novel 1-benzoyl 4-phenoxypiperidine scaffold was discovered to disrupt the β-catenin/BCL9 protein-protein interaction (PPI) with a Ki of 0.96 μM in AlphaScreen competitive inhibition assays and displayed good selectivity for β-catenin/BCL9 over β-catenin/E-cadherin PPIs. The binding mode of new inhibitors was characterized by structure-activity relationship and site-directed mutagenesis studies. Protein pull-down assays indicate that this series of compounds directly binds with β-catenin. Cellular target engagement and co-immunoprecipitation experiments demonstrate that ZL3138 binds with β-catenin and disrupts the β-catenin/BCL9 interaction without affecting the β-catenin/E-cadherin interaction in living cells. Further cell-based studies show that ZL3138 selectively suppresses transactivation of Wnt/β-catenin signaling, regulates transcription and expression of Wnt target genes, and inhibits the growth of Wnt/β-catenin-dependent cancer cells.