A series of five 3,5-bisarylidene-4-piperidones designed as analogs of curcumin and their twenty five fatty acid conjugates were synthesized as candidate anticancer agents. The fatty acid conjugates were designed for efficient delivery of these compounds at the targeted cancer sites. The cytostatic potential of these compounds was evaluated against three representative cancer cell lines namely murine leukemic L1210 cells, and human T-lymphocyte CEM cells and cervical HeLa cells. Most compounds were found to exhibit significant anti-cancer activity in vitro. QSAR studies indicated electrophilicity of these compounds towards cellular nucleophiles may have a key role to play in their cytostatic activity. Representative compounds were also tested for topoisomerase IIα inhibitory potential, which indicated strong catalytic inhibition of the enzyme in vitro. The data showed that the fatty acid conjugates also possessed robust antioxidant activity in multiple analyses. This study also indicated that these compounds prompted significantly lower cellular damage in human fibroblasts than a currently used cancer drug sorafenib in vitro. The wide spectrum of anticancer action, supplemented with antioxidant potential along with non-toxic manifestations, certainly augment the anticancer candidacy of the novel fatty acid conjugates.