Cancer still represents a major global health problem. All currently available anticancer agents have disadvantages like resistance or side effects. Therefore, introduction of novel anticancer agents is needed. Intrigued by the high success rate for natural products-based drug discovery, we designed and synthesized antiproliferative chemical entities as hybrids of two natural products; 3,5,4′-trimethoxystilbene and 5,6,7-trimethoxyflavone. To probe the spectrum of the synthesized compounds, in vitro evaluation was conducted against nine panels representing major cancer diseases. The results revealed the hybrid analogs 4f, 4h, 4k and 4q as promising broad-spectrum anticancer lead compounds eliciting high growth inhibition of several cell lines representing multiple cancers diseases. Evaluation of the promising lead compounds against normal human cell lines suggested a selective cytotoxic effect on cancer cells. Mechanistic investigation of the cytotoxic activity of compound 4f in human cervical cancer HeLa cells showed that it triggers cell death through induction of apoptosis. As a whole, this study presents the natural products hybrid analogs 4f, 4h, 4k and 4q as potential lead compounds for further development of novel anticancer therapeutics. Display omitted •Design, synthesis and in vitro antiproliferative evaluation of 3,5,4′-trimethoxystilbene-5,6,7-trimethoxyflavone hybrids.•Compounds 4f, 4h, 4k and 4q elicited promising broad spectrum antiproliferative activity.•Compounds 4f, 4h, 4k and 4q were more selective to human cancer cells rather than normal human cells.•Compound 4f triggered cell death via induction of apoptosis in HeLa cells.•Compounds 4f, 4h, 4k and 4q might be potential leads for development of natural-products based anticancer agents.