Background: Malathion (Mal), a commonly used organophosphate insecticide, causes significant lung damage through oxidative stress, inflammation, and stimulation of pulmonary fibrosis. Curcumin (Cur), a natural polyphenolic molecule, possesses strong antioxidant, anti-inflammatory, and antifibrotic functions. Objective: This work aimed to evaluate the protective effects of Cur against Mal-induced lung injury in rats by modulating the Nrf2/HO-1, NF-κB/TNF-α, and COX-2 signaling pathways. Methods: Twenty-four adult male Sprague Dawley rats were randomly divided into four equal groups: control, Cur-treated (150 mg/kg/day), Mal-treated (100 mg/kg/day), and Mal+Cur (received Cur followed by Mal after 3 h) groups. Both Mal and Cur were administered orally via gavage for four weeks. Oxidative stress markers, inflammatory mediators, and fibrotic alterations were assessed in lung tissues using biochemical and histological methods. The expression of key signaling molecules, including Nrf2/HO-1 (antioxidant response), NF-κB/TNF-α (inflammatory response), and COX-2 (pro-inflammatory enzyme), was measured via immunohistochemistry and quantitative PCR. Results: Compared to the control group, Mal exposure led to marked oxidative damage, evidenced by elevated Malondialdehyde (MDA) levels (p < 0.0001) and decreased superoxide dismutase (SOD) and acetylcholinesterase (AChE) levels (p < 0.0001). This was accompanied by increased expression of pro-inflammatory (TNF-α, IL-1β, IL-6, and PGE2 (p < 0.0001)) and pro-fibrotic (hydroxyproline) markers, and significant histopathological alterations. Co-administration of curcumin significantly attenuated these effects, restoring AChE activity, enhancing Nrf2/HO-1/ antioxidant signaling, and suppressing NF-κB/TNF-α and COX-2 inflammatory pathways. Conclusion:: These data demonstrate that curcumin protects against malathion-induced lung injury by modulating oxidative stress, inflammation, and fibrosis-related pathways, highlighting its therapeutic potential for mitigating organophosphate-induced respiratory damage