Drug resistance and inability to distinguish between cancerous and non-cancerous cells are important obstacles in the treatment of cancer. Zinc oxide nanoparticles (ZnO NPs) is now emerging as a crucial material to challenge this global issue due to its tunable properties. Developing an effective, inexpensive, and eco-friendly method in order to tailor the properties of ZnO NPs with enhanced anticancer efficacy is still challenging. For the first time, we reported a facile, inexpensive, and eco-friendly approach for green synthesis of ZnO-reduced graphene oxide nanocomposites (ZnO-RGO NCs) using garlic clove extract. Garlic has been playing one of the most important dietary and medicinal roles for humans since centuries. We aimed to minimize the use of toxic chemicals and enhance the anticancer potential of ZnO-RGO NCs with minimum side effects to normal cells. Aqueous extract of garlic clove was used as reducing and stabilizing agent for green synthesis of ZnO-RGO NCs from the zinc nitrate and graphene oxide (GO) precursors. A potential mechanism of ZnO-RGO NCs synthesis with garlic clove extract was also proposed. Preparation of pure ZnO NPs and ZnO-RGO NCs was confirmed by powder X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and dynamic light scattering (DLS). The in vitro study showed that ZnO-RGO NCs induce two-fold higher cytotoxicity in human breast cancer (MCF7) and human colorectal cancer (HCT116) cells as compared to pure ZnO NPs. Besides, biocompatibility of ZnO-RGO NCs in non-cancerous human normal breast (MCF10A) and normal colon epithelial (NCM460) cells was higher than those of pure ZnO NPs. This work highlighted a facile and inexpensive green approach for the preparation of ZnO-RGO NCs with enhanced anticancer activity and improved biocompatibility.