A new library of substituted amide derivatives of coumarin-1,2,4-thiadiazoles (12a-j) was synthesized, and their chemical structures were confirmed by spectroscopic techniques. The synthesized compounds were evaluated for their in vitro anticancer activity against a panel of human cancer cell lines, including PC3 (prostate), A549 (lung), MCF-7 (breast), and SiHa (cervix), using the MTT assay, with etoposide as the positive control. The compounds exhibited good to moderate anticancer activity, with IC50 values ranging from 0.11 ± 0.029 to 9.12 ± 4.67 µM, whereas etoposide showed IC50 values ranging from 2.11 ± 0.024 to 3.11 ± 0.11 µM. Among the synthesized derivatives, 12a, 12b, 12c, and 12d displayed remarkable anticancer potency.