A series of (E) 4H-pyrano[3,2-h]quinoline-3-carbonitrile (5a–f) and (E) ethyl 4H-pyrano[3,2-h]quinoline-3 carboxylate (6a–f) derivatives were synthesized by interaction of (E) 2-(4-chloro/bromo/fluorostyryl)-8-hydroxyquinoline (3a–c) with a-cyano-p-chloro/bromocinnamonitriles (4a,b) and ethyl a-cyano-p-chloro/bromocinnamates (4c,d), respectively. Structures of these compounds were established on the basis of IR, 1 H NMR, 13C NMR, 13C NMR–DEPT, 13C NMR– APT, and MS data. The new compounds were evaluated for antitumor activities against three different human tumor cell lines MCF-7, HCT, and HepG-2. The results of antitumor evaluation revealed that compounds 5a,d and 6a,c,d inhibited the growth of cancer cells compared to Vinblastine. The structure–activity relationships were discussed.