A new series of N-substituted diarylidenepiperidin-4-ones was synthesized and screened for their possible anticancer activity at the NCI Developmental Therapeutic Program. Almost all the synthesized compounds showed more potent antiproliferative activity than curcumin. The most active compound in this study was 3,5-bis(4-bromobenzylidene)-1-propanoylpiperidin-4-one (8a) with MGMID GI50, TGI, and LC50 values of 0.35, 1.62 and 9.12 µM, respectively. Compound 8a displayed broad spectrum antiproliferative activity with GI50 values below 1 µM in 81% of the tested cell lines and was found to be two folds more potent than EF-24. A detailed study of the structure activity relationship of the N-substitution was also described.