The synthesis of 4-arylidene-3-methyl-1-(4-(5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl)-1H-pyrazol-5(4H)-ones was described as a successful multi-component condensation reaction. Thiazole and pyrazolone are simultaneously formed during the synthesis process, and an active methylene group is condensed with an aryl aldehyde using the Knoevenagel reaction. Some of the remarkable characteristics of this technique are quick reaction times, gentle environmental conditions, straightforward operation, streamlined purification, and acceptable yields. The newly synthesized compounds were assessed as anticancer agents on HCT-116, HepG-2, and MCF-7 human cancer cells and one human healthy cell line (BJ-1) using the LDH assay. The most active compounds were examined as VEGFR inhibitors. Moreover, a molecular docking study was conducted to identify the binding interactions of the most potent candidates (6e, 6g, and 6i), within the active sites of the Vascular Endothelial Growth Factor Receptor (VEGFR-2/KDR) kinase. Compounds 6e, 6g and 6i exhibited the most favorable binding interaction scores with the targeted enzyme. Furthermore, the bioassay results demonstrated that the three selected compounds (6e, 6g, and 6i) displayed highly promising activities by significantly inhibiting VEGFR-2 kinase at very low IC50 values compared to their cytotoxicity IC50 outcomes.