Several curcumin analogues (C01-C03) were prepared in green solvent (water-glycerol; 2:1 v/v) with boric acid (10% mol solution in glycerol). All the compounds were characterized by spectroscopical techniques including infrared (IR), nuclear magnetic resonance (1H and 13C NMR) and mass spectral data. In accordance with the National Cancer Institute (NCI US) protocol, the curcumin analogues (C01-C03) were evaluated at 10 µM against 60 NCI cancer cell lines. One of the compounds (C01) was further evaluated in five dose assays. 1-(3,5-Bis((E)-4‑hydroxy-3-methoxystyryl)-1H-pyrazol-1-yl)-2-((4-chlorophenyl)amino)ethan-1-one (C01), exhibited a lethal effect on HL-60(TB) (PGI = 111.56) and MDA-MB-435 (PGI = 107.11). Additionally, the compound (C01) exhibited good inhibitory action against forty cancer cell lines with PGI 100 to >68 percent and moderate inhibitory action against fourteen cancer cell lines. The compound (C01) exhibited promising anticancer activity in five dose assays, with a mean GI50 value of 3.31 µM. Against the leukemia cell line SR, the compound showed the best response, with a GI50 value of 0.341 µM. All the curcumin analogous (C01-C03) demonstrated efficient binding against the AZD9291 binding site of EGFR with docking score of −6.849 to −7.444 kcal/mol. The compounds (C01-C03) demonstrated three H-bonds with the residue Met793, Lys728 and Asn842, and two halogen bonds with the residue Lys745 and Glu762. The MD simulation studies was performed against the curcumin analogue (C01) and compared with the standard drug gefitinib.