A series of 1-aryl, 5-(phenoxy-substituted)aryl-1,4-pentadien-3-one derivatives were synthesized and evaluated for anticancer activity. Amongst the synthesized ethers, 4A and 4Y exhibited substantial antiproliferative activity with IC50 values ranging from 6.6–8.6 mmol L1 against a variety of human cancer cell lines. Preliminarily mechanism of antitumor action of 4A by DNA Ladder, Annexin V/PI double staining and related studies indicated growth inhibition of PC3, BGC-823 and Bcap-37 cells by induction of tumor cells apoptosis.