The objective of the current study is to evaluate the potency of halogen-furan-2(5 H )-one-type derivatives against human cancer cell lines. Four known bromofuran-2(5 H )-one-type derivatives, as well as five new and two known bromo-4-(phenylamino)furan-2(5 H )-one-type compounds and six novel and two known halogen-4-alkyl-5-phenyl-3-(phenylamino)furan-2(5 H )-one-type derivatives, were synthesized and evaluated for their anticancer activity against prostate (PC-3) and colon (HCT-116) human cancer cell lines. The results showed that only the bromofuran-2(5 H )-ones were cytotoxic in both cell lines. Three of these displayed particularly useful antiproliferative activities, in both cancer cells evaluated. ( E )-5-(Bromomethylene)furan-2-(5 H )-one was the most active against PC-3 (IC 50 0.93 ± 0.02 μM) while 3,4-dibromofuran-2(5 H )-one was the most active against HCT-116 (IC 50 0.4 ± 0.04 μM). Furthermore, flow cytometry studies revealed that the bromofuran-2(5 H )-ones induced cell death by apoptosis. Also, it was found that the cytotoxic furanones induced lipid peroxidation, determined by TBARS assay. Thus, cytotoxicity of the active compounds could be associated with ROS production. Additionally, it must be taken into account that all cytotoxic compounds contain an electrophilic carbon atom in position 4, which can explain, through a non-specific reactivity with nucleophiles, the cytotoxic activity of these compounds. Graphic abstract