A series of halogenated derivatives of natural flavonoids: baicalein and chrysin were designed and investigated as possible ligands for the catalytic subunit of tumor‐associated human kinase CK2. Thermal shift assay method, in silico modeling, and high‐performance liquid chromatography‐derived hydrophobicity together with IC₅₀ values determined in biochemical assay were used to explain the ligand affinity to the catalytic subunit of human protein kinase CK2. Obtained results revealed that substitution of baicalein and chrysin with halogen atom increases their binding affinity to hCK2α, and for 8‐chlorochrysin the observed effect is even stronger than for the reference CK2 inhibitor—4,5,6,7‐tetrabromo‐1H‐benzotriazole. The cytotoxic activities of the baicalein and chrysin derivatives in the in vitro model have been evaluated for MV4‐11 (human biphenotypic B myelomonocytic leukemia), A549 (human lung adenocarcinoma), LoVo (human colon cancer), and MCF‐7 (human breast cancer) as well as on the nontumorigenic human breast epithelial MCF‐10A cell lines. Among the baicalein derivatives, the strongest cytotoxic effect was observed for 8‐bromobaicalein, which exhibited the highest activity against breast cancer cell line MCF‐7 (IC₅₀ 10 ± 3 μM). In the chrysin series, the strongest cytotoxic effect was observed for unsubstituted chrysin, which exhibited the highest activity against leukemic cell line MV4‐11 (IC₅₀ 10 ± 4 μM).