<p>This study evaluated the neuroprotective effects of pomegranate peel polyphenols (PPEP) and their nanoparticles in a rodent model of DOX-induced neurotoxicity. Polysorbate 80- coated PPEP poly (lactic-co-glycolic acid) nanoparticles (PLGA-NP) were synthesized by the double emulsification solvent evaporation technique. Successful encapsulation of PPEP was confirmed by Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), and Differential Scanning Calorimetry (DSC) analyses. Neurotoxicity was induced in male Wistar rats by administering DOX (2.5&#xa0;mg/kg bw) once every five days i.p. Treatment with PPEP and its nanoparticles (10&#xa0;mg/kg bw equivalent polyphenols p.o) was performed for 60 days. At the end of the treatment, the Morris water maze test was performed to assess cognitive function, and rat brains were removed for further histopathological, biochemical, and molecular analyses. To understand the pathophysiology of DOX-induced neurodegeneration, oxidative stress, inflammatory, and apoptosis markers were assessed by ELISA and Western blotting. Treatment with an encapsulated pomegranate peel polyphenolic extract reduced oxidative stress as evidenced by increased catalase and superoxide dismutase levels and decreased malondialdehyde levels. Mechanistically, it alleviated inflammation by downregulating the expression of pro-inflammatory markers NF-kB (p65) and TNF-α; restored acetylcholine levels, and reduced apoptosis markers (caspase 3 and cytochrome c). Furthermore, histopathological findings supported the attenuation of DOX-induced pathologies in the hippocampus and cortex regions of the brain. Enhanced bioavailability and efficacy of polyphenols were observed for the encapsulated extract. Our results demonstrate the neuroprotective potential of free and encapsulated PPEP in DOX-induced neurotoxicity and highlight the effective valorization of pomegranate peel waste for health applications.</p> Graphical abstract <p></p>