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Cancer remains a global health burden prompting affordable, target-oriented, and safe chemotherapeutic agents to reduce its incidence rate worldwide. In this study, a rapid, cost-effective, and green synthesis of titanium dioxide (TiO₂) nanoparticles (NPs) has been carried out; Ex vivo and in vivo<em> </em>evaluation of their safety and anti-tumor efficacy compared to doxorubicin (DOX), a highly efficient breast anti-cancer agent but limited by severe cardiotoxicity in many patients.<strong> </strong>Thereby,<strong> </strong>TiO₂ NPs were eco-friendly synthetized using aqueous leaf extract of the tropical medicinal shrub <em>Zanthoxylum armatum </em>as a reducing agent. Butanol was used as a unique template. TiO₂ NPs were physically characterized by ultraviolet-visible (UV–Vis) spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM), scanning electron microscope (SEM), X-ray powder diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR) as routine state-of-the art techniques. The synthesized TiO₂ NPs were then evaluated for their cytotoxicity (by MTT, FACS, and oxidative stress assays) in 4T1 breast tumor cells, and their hemocompatibility (by hemolysis assay). In vivo anti-tumor efficacy and safety of the TiO₂ NPs were further assessed using subcutaneous 4T1 breast BALB/c mouse tumor model.<strong> </strong>The greenly prepared TiO₂ NPs were small, spherical, and crystalline in nature. Interestingly, they were hemocompatible and elicited a strong DOX-like concentration-dependent cytotoxicity-induced apoptosis both ex vivo and in vivo (with a noticeable tumor volume reduction). The underlying molecular mechanism was, at least partially, mediated through reactive oxygen species (ROS) generation (lipid peroxidation). Unlike DOX (<em>P</em> < 0.05), it is important to mention that no cardiotoxicity or altered body weight were observed in both the TiO₂ NPs-treated tumor-bearing mouse group and the PBS-treated mouse group (<em>P</em> > 0.05). Taken together, <em>Z. armatum</em>-derived TiO₂ NPs are cost-effective, more efficient, and safer than DOX. The present findings shall prompt clinical trials using green TiO₂ NPs, at least as a possible alternative modality to DOX for effective breast cancer therapy.