Wnt pathway is vital for survival of cancer-initiating cells. β-catenin plays a crucial role in Wnt pathway through interaction with TCF-4 to transcribe oncogenes. β-catenin activation suppresses immune cell infiltration into cancer cells and promotes resistance to chemotherapeutic drugs. In order to target Wnt/TCF-4/β-catenin pathway, a novel series of pyrimidothiazino-, dihydropyrimidotriazepino- and 1,3,4 thiadiazolopyrimido-indole hybrids were designed, synthesized and evaluated for their β-catenin/TCF-4 inhibitory and apoptotic inducing activities. Cytotoxicity of the synthesized hybrids was evaluated against HCT-116, A549 and HepG2 cell lines. Of the synthesized hybrids, 6a, 8b and 12b hybrids elicited superior cytotoxic activity compared to quercetin against the tested cell lines. These hybrids were able to significantly suppress β-catenin and its down-stream signaling target TCF-4 in a dose-dependent manner in HCT-116 cell line. They up-regulated p53, caspase-3, caspase-8, caspase-9 levels and Bax protein expression as well as down-regulated Bcl-2 protein expression. They successfully arrested cell cycle in pre-G1 phase and G0/G1 phase. The synthesized hybrids achieved efficient binding pattern in molecular docking study and have acceptable drug likeness characters.