A series of chalcone imide derivatives, 4'-aminochalcones-based dichloromaleimides, was synthesized from the reaction of 1-(4-acetylphenyl)-3,4-dichloro-1H-pyrrole-2,5-dione with various substituted aldehydes, or by treating 4'-aminochalcone with 3,4-dichlorofuran-2,5-dione in an alternative path. The structures of chalcone imide derivatives were established using IR, 1H NMR, 13C NMR, and mass spectroscopy. Antiproliferative effects of the newly synthesized compounds have been screened on two human cancer types via the MTT assay. Compounds with p-tolyl-1H-pyrrole-2,5-dione, and 4-bromophenyl-1H-pyrrole-2,5-dione derivatives, are highly active on the human liver cancer (HepG-2). On the other hand, all compounds were found to be more effective against breast cancer cells (MCF-7) than the positive control doxorubicin. The results of this work provide a basis for further research of selected chalcone-imide moiety as antiproliferative agents.