•ZnONPs were biologically synthesized using palm fruit extract as reducing and stabilizing agent.•The size and shape of bio-synthesized ZnONPs depends on the concentrations of the extract.•In vitro studies on ZnONPs induce a significant reduction of Bcl-2 expression on MCF-7 cells.•In vivo evaluation verified the biocompatibility of DOX-ZnONPs, no significant toxicity on blood stream as well. The green synthesis of zinc oxide nanoparticles (ZnONPs) using Borassus flabellifer fruit extract was characterized by UV–visible spectroscopy, FT-IR, XRD, TEM, Zeta potential and EDS analysis. The UV–visible spectrum showed an absorption peak at 368nm that reflects surface Plasmon resonance (SPR) ZnONPs. TEM photograph showed that the green synthesized ZnONPs were porous in nature and rod like structure with an average size of 55nm. The Zeta potential value of −21.5mV revealed the surface charge of green synthesized ZnONPs. In this study, we examined the synthesized DOX-ZnONPs exhibited a dose-dependent cytotoxicity against MCF-7 and HT-29. The inhibitory concentration (IC50) was found to be 0.125μgmL−1 for MCF-7 and HT-29 cells. An induction of apoptosis was evidenced by nuclear stain Hoechst 33258. In vivo toxicity assessment showed that DOX-ZnONPs have low systemic toxicity in murine model system. The results prove that the DOX-ZnONPs has low toxicity and high therapy efficacy, which provides convincing evidence for the green biosynthesized ZnO as a promising candidate for a drug delivery system.