Fourteen novel bis-carboxamide derivatives of 4-pyrones were designed and synthesized via Ugi four-component reactions of 4-pyrone carbaldehydes, aromatic amines, isocyanides and carboxylic acids. The cytotoxic activity of synthesized derivatives was evaluated against LS180, MCF-7 and HL-60 cell lines using MTT reduction assay. Synthesized compounds demonstrated strong cytotoxic potential in HL-60 cell line. Compound 12n was the most potent derivative with IC50 values of 16.1, 9.1 and 13.8 μM in LS180, MCF-7 and HL-60 cells, respectively. The results of MLR-QSAR study indicated that topological property of these derivatives directly influenced the cytotoxic potential in HL-60 cell line. Docking study of compounds, conducted for ATP binding site of Src tyrosine kinase, demonstrated the key H-bond interaction with Met 347 of the hinge region.