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Fisetin (FIS) is a natural flavonoid compound with promising anti-cancer, antioxidant, and neuroprotective properties. Despite these benefits, the low aqueous solubility of fisetin prevents its delivery through intravenous administration resulting in poor bioavailability. Hence, it is important to develop suitable delivery approaches to boost the overall performance of FIS and make it suitable for various medical applications. In this study, we formulated FIS-loaded polymannose (PM) nanoparticles (FIS-PM NPs) to increase their solubility and therapeutic efficacy. In addition, we have nanotized the FIS (Nano FIS) using the antisolvent precipitation method and compared its efficacy with the FIS. The nanoformulations FIS-PM NPs and nanotized FIS were characterized using different techniques such as Dynamic Light Scattering (DLS), UV-vis spectroscopy, scanning electron microscope (SEM), Fourier transform infrared (FTIR) spectroscopy, and X-ray diffraction (XRD). Furthermore, the anticancer effect of FIS and its nanoformulations were tested in breast cancer cell lines (MDA-MB-231). The apoptotic potential of the nanoformulations was examined using different staining techniques and Annexin-V apoptosis assay using flow cytometry. The cell cycle analysis was performed to check the exact mechanism of cell death. The FIS-PM NPs revealed an average size of 250 nm, while Nano FIS showed an average size of 139 nm. FIS-loaded PM NPs showed an encapsulation efficiency of 88% and a drug content of 37%. In vitro drug release studies of the FIS-PM NPs showed a concentration-dependent controlled release of the FIS followed by an initial burst release of ≈ 40 % in phosphate-buffered saline (PBS) at different pH. FIS-PM NPs treated cells showed more cytotoxicity in comparison with nanotized FIS and FIS. We observed more apoptosis in FIS-PM NPs and Nano FIS treated cells compared to FIS and control cells as early as 24 h after the treatment. The cell cycle arrest was seen in the G1 phase of the cells treated with FIS-PM NPs and Nano FIS. In conclusion, the anticancer potential of FIS-PM NPs and Nano FIS has improved in MDA-MB-231 compared to raw FIS which can be attributed to the enhanced solubility of FIS. [ABSTRACT FROM AUTHOR]