A new series of 3,4,5-trimethoxyphenyl thiazole pyrimidines has been synthesized and biologically evaluated for its in vitro anticancer activity. Compounds4a,4b, and4hwith substituted piperazine showed the best antiproliferative activity. In the NCI-60 cell line screening, compound4bshowed promising cytostatic activity against multiple cell lines. Notably, it elicited a GI value of 86.28% against the NSCL cancer cell line HOP-92 at a 10 μM dose. Compounds4aand4hat 10 μM showed promising GI values of 40.87% and 46.14% against HCT-116 colorectal carcinoma and SK-BR-3 breast cancer cell lines, respectively. ADME-Tox prediction of compounds4a,4b,and4hrevealed their acceptable drug-likeness properties. In addition, compounds4a,4b, and4hshowed a high probability of targeting kinase receptors via Molinspiration and Swiss TargetPrediction.