In this paper we report an efficient and general synthesis of substituted 3-diethoxyphosphorylnaphtho [2,3-b]furan-4,9-diones and 3-diethoxyphosphorylbenzo [f]indole-4,9-diones which integrate the natural 1,4-naphtalenedione scaffold, present in several anticancer agents with the phosphonate moiety. The cytotoxicity of such hybrid molecules was tested against two leukemia cell lines, HL-60 and NALM-6 and against a breast adenocarcinoma MCF-7 cell line. Selected compounds were also tested on normal human cells: HUVEC and MCF-10A. In general, naphthofuran-4,9-diones showed much higher cytotoxic activity (IC50 values below 10 μM) than benzoindole-4,9-diones. The most promising 2-(2-chlorophenyl)-3-diethoxyphosphorylnaphtho [2,3-b]furan-4,9-dione, with the highest cytotoxic activity in the MTT test, was chosen for further evaluation of its anticancer potential. This compound, tested on HL-60 and MCF-7 cells inhibited cell proliferation, generated DNA damage and induced apoptosis. The suggested mechanism of its cytotoxic activity was the generation of intracellular reactive oxygen species and the induction of mitochondrial membrane potential dissipation.