Acute kidney injury (AKI) is a clinical syndrome associated with the incidence of rhabdomyolysis (RM). The current study was carried out to evaluate whether selenium nanoparticles (SeNPs) can protect against the glycerol-induced AKI model. Rats were distributed into four equal groups (n = 7): the control group (G1), SeNPs group (G2), AKI group (G3), and SeNPs+AKI group (G4). Rats in G1 were intramuscularly injected with physiological saline (0.9% NaCl). Rats in G2 were gavaged with SeNPs (0.1 mg/kg) for 14 days. Rats in G3 were intramuscularly injected with 50% glycerol (10 ml/kg). Rats in G4 were administered with SeNPs for 14 days and then injected with glycerol, as in G3. Glycerol-injected rats showed a significant increase in the kidney relative weight, as well as in the serum urea, creatinine, Kim-1, and renal malondialdehyde, nitric oxide, TNF-α, IL-1β, cytochrome c, Bax, and caspase-3 levels. In addition, a significant decrease in glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase was recorded in the renal tissue. Selenium nanoparticles reduced the biochemical, molecular, and histological changes produced by glycerol. Overall, our results suggest that selenium nanoparticles could be used to protect against AKI development via antioxidant, anti-inflammatory, and anti-apoptotic activities.