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[Display omitted] • A novel series of ethylidenehydrazineylthiazol-4(5 H)-ones were generated using eco-friendly one-pot multicomponent synthetic techniques. • The anticancer potentials towards eleven cancer cell lines were evaluated. • The IC 50 values against MDA-MB-468 and FaDu cell lines were recorded. • 4k exhibited the highest inhibitory activity against both EGFR-WT and EGFR-T790M. • The cell cycle analysis, proapoptotic markers (p53, BAX, caspase 3, caspase 6, caspase 8, and caspase 9), and the anti-apoptotic key marker (BCL-2) were measured for 4k. A novel series of ethylidenehydrazineylthiazol-4(5 H)-ones were synthesized using various eco-friendly one-pot multicomponent synthetic techniques. The anticancer activity of compounds (4a-m) was tested against 11 cancer cell lines. While the IC 50 of all compounds was evaluated against the most sensitive cell lines (MDA-MB-468 and FaDu). Our SAR study pinpointed that compound 4a , having a phenyl substituent, exhibited a significant growth inhibition % against all cancer cell lines. The frontier anticancer candidates against the MDA-MB-468 were also examined against the wild EGFR (EGFR-WT) and mutant EGFR (EGFR-T790M) receptors. Most of the synthesized compounds exhibited a higher inhibitory potential against EGFR-T790M than the wild type of EGFR. Remarkably, compound 4k exhibited the highest inhibitory activity against both EGFR-WT and EGFR-T790M with IC 50 values (0.051 and 0.021 µM), respectively. The pro-apoptotic protein markers (p53, BAX, caspase 3, caspase 6, caspase 8, and caspase 9) and the anti-apoptotic key marker (BCL-2) were also measured to propose a mechanism of action for the compound 4k as an apoptotic inducer for MDA-MB-468. Investigation of the cell cycle arrest potential of compound 4k was also conducted on MDA-MB-468 cancer cells. We also evaluated the inhibitory activities of compounds (4a-m) against both EGFR-WT and EGFR-T790M using two different molecular docking processes. [ABSTRACT FROM AUTHOR]