The growing interest in using plant extracts for the biogenic synthesis of zinc oxide nanoparticles (ZnO NPs) stems from their facile, eco-friendly, and biologically safe approach instead of chemical routes. For the first time, ZnO NPs were successfully biosynthesized using Rhus coriaria fruit aqueous extract as a reducing and capping agent. Characterization revealed that the biosynthesized ZnO NPs possessed a maximum absorbance of approximately 359 nm and closely resembled the hexagonal ZnO wurtzite crystalline structure, with an average crystalline size of 16.69 nm. The transmission electron microscope (TEM) showed the presence of spherical and hexagonal morphologies, with an average grain size of 20.51 ± 3.90 nm. Moreover, the elemental composition of the synthesized ZnO NPs was assessed via energy-dispersive X-ray spectrometry (EDX), and the presence of phytocompounds on their surface was subsequently verified through FT-IR analysis. The ζ-potential of ZnO NPs was recorded at − 19.9 ± 0.1663 mV. Regarding anti-cancer properties, ZnO NPs were found to possess potent anti-tumor effects on MCF-7 and MDA-MB-231 breast cancer cells. Their efficacy was dose-dependent, with IC50 values ranging from 35.04–44.86 μg/mL for MCF-7 and 55.54–63.71 µg/mL for MDA-MB-231 cells. Mechanistic studies in MDA-MB-231 cells revealed apoptosis induction, validated by DAPI staining, confocal microscopy, and Annexin V/PI staining, showing apoptosis by 12.59% and 81.57% at ½ IC50 and IC50 values, respectively. Additionally, ZnO NPs were observed to provoke S-phase arrest and inhibit colony-forming and metastatic potential by modulating apoptosis and metastasis-related genes. This study unravels new insights into how ZnO NPs provoke cancer cell death and inhibit metastasis, revealing new prospects in cancer nanotechnology.