The phosphatidylinositol 3‐kinase/protein kinase B (PI3K/AKT) pathway is a crucial pathway in cancer pathogenesis. Novel derivatives of 4,6‐dihydroxy‐2‐quinolone‐3‐carboxamides were synthesized as potential PI3Kα inhibitors. Derivatives’ chemical identity was approved using 1H‐NMR, 13C‐NMR, FTIR, and MS. Cytotoxicity was evaluated on the breast (MCF‐7) and colon cancer (HCT‐116) cell lines using the CCK8 assay. Apoptosis was assessed by Annexin‐PI staining. Western blotting was employed to assess the expression of BcL2, Bax, and the phosphorylation status of AKT. Data revealed that compounds exhibited a dose‐response cytotoxic effect. Compounds 8 b and 8 f showed the lowest IC50 on all cell lines and highest apoptosis levels that were associated with lower BcL2/Bax ratios. Western blot results showed a significant inhibition of pAKT in the treated cells, which could be attributed to PI3Kα inhibitory effects of 8 b and 8 f. In conclusion, our findings indicate that 8 b and 8 f are drug‐like chemical compounds that possess promising anticancer effects.