Nonsteroidal anti-inflammatory drugs (NSAIDs), involving Meloxicam, are associated with significant hepato-renal toxicity due to their competitive nonelective inhibition of cyclooxygenase enzymes. This study hypothesizes that N-acetyl cysteine (NAC), with its several pleiotropic effects such as anti-inflammatory, antioxidant and anti-apoptosis, mitigates the hepato-renal toxicity induced by Meloxicam. Fifty albino rats were blindly and randomly divided into five groups: a control (saline), vehicle control (Tween 80), Meloxicam-treated, NAC-treated, and a combination treatment group (Meloxicam + NAC). The study evaluated biochemical parameters, oxidative stress markers, histological and immunohistochemical changes in liver and kidney tissues. This study fills a significant gap in understanding how NAC can counteract NSAID (Meloxicam) toxicity, with potential clinical implications for safer long-term NSAID use. NAC administration significantly reversed the elevated levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), urea, and creatinine induced by Meloxicam toxicity. Additionally, oxidative stress markers such as malondialdehyde (MDA) were significantly reduced, while antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) showed significant improvement in the NAC-treated groups (p ≤ 0.05). Histological and immunohistochemical assessment confirmed these findings, showing reduced tissue damage and apoptosis. In conclusion, the obtained results suggest that NAC protects against Meloxicam-induced hepato-renal toxicity, with a significant reduction in oxidative stress and inflammation, supporting its potential therapeutic role in conjunction with NSAIDs treatment protocols.