A series of fifteen novel dihydropyrimidinone hybrid compounds were synthesized in good yields via a multicomponent reaction combined with the Huisgen reaction. The antiproliferative activity was investigated against nine tumor cell lines, and four hybrid compounds (TGI < 10 μM) showed promising antiproliferative activity against the tumor cell lines OVCAR-3 (ovarian), UACC-62 (melanoma) and U251 (glioma). Several hybrid compounds assayed have high TGI values (TGI 147.92–507.82) for the human keratinocyte cell line (HaCat), which reveals selectivity to cancer cells.