Background: Flavonoids are naturally occurring compounds with versatile health-promoting effects against various diseases. Objective: To synthesize and evaluate biological activity of novel flavone derivatives against cancer. Methods: A new series of 2-hydroxy-α,β-unsaturated ketones 2a-h was synthesized via the reaction of N-substituted-indole-3-carboxaldehydes 1a-h with 2-hydroxy acetophenone in the presence of piperidine. The oxidative cyclization of 2a-h using hydrogen peroxide/KOH and/or dimethyl sulfoxide/I2 produced the corresponding 2-(N-substituted-1H-indol-3-yl)-3-hydroxy-4H-chromen-4-ones 3a-h and 2-(N-substituted-1H-indol-3-yl)-4H-chromen-4-ones 4a-h respectively. Anti-proliferative activities for synthesized series were investigated against HCT-116 colon and MCF-7 breast cancer cell lines. Molecular downstream effects were evaluated using RT-PCR. Moreover, molecular docking was carried out to pinpoint the binding mode of the most active compounds into the active site of Akt enzyme (PDB ID: 3QKK). Results: All compounds exhibited anti-proliferative activity range of 52-97% and 67.2-99% against HCT-116 and MCF-7 respectively. Compounds 3b, 3h, 3g and 4h had minimal inhibitory effect on normal BJ1 cells indicating their safety profile. Compounds 3b and 4h in particular exhibited the most potent antiproliferative activity against HCT116 and MCF7, meanwhile compounds 3g, 3h and 4g showed potent to moderate activity. Compound 3b had IC50 of 78.3 µM and 53.9 µM against HCT-116 and MCF-7 respectively with comparable IC50 for doxorubicin of 65.1 µM and 45.02 µM respectively. Compound 3b exhibited significant down-regulation for Akt and significant up-regulation of CAS9 and CDKN1genes in all tested cell lines. Conclusion: The synthesized flavone derivatives and particularly compound 3b exhibited promising anticancer activity through Akt inhibition.