Manganese (Mn) is an essential trace element crucial for antioxidant defense, metabolism, and neuronal function, yet both deficiency and excess may induce oxidative stress and organ-specific damage. This study investigated the effects of dietary manganese exclusion and replacement of standard MnCO3 with Mn2O3 nanoparticles on redox status and oxidative damage in rats. Twenty-four male Wistar rats were divided into three groups: control (K) receiving 65 mg/kg Mn as MnCO3, manganese-deficient (B), and nanoparticle-supplemented (N) receiving 65 mg/kg Mn as Mn2O3 nanoparticles. After 12 weeks, tissues were analyzed for oxidative stress markers and antioxidant enzyme activities. Manganese deficiency resulted in decreased plasma SOD activity, increased lipid peroxidation, and severe oxidative–nitrosative damage in the brain and jejunum, despite hepatic compensatory mechanisms. Mn2O3 nanoparticle supplementation enhanced hepatic and renal antioxidant capacity, reducing oxidative damage in these organs. However, nanoparticles induced pronounced neurotoxicity, characterized by GSH depletion, elevated DNA damage (8-OHdG), protein nitration (3-NT), and caspase activation in brain tissue. These findings demonstrate that while Mn2O3 nanoparticles offer improved bioavailability and hepatorenal benefits, they pose significant neurotoxic risks, necessitating caution in dietary supplementation strategies.