Leptadenia reticulata, a plant with a history of use in traditional medicine, was evaluated for its phytochemical composition and anti-inflammatory potential. Roots were collected, authenticated, and subjected to extraction using different solvents—ethanol, aqueous ethanol (80:20), hexane, and ethyl acetate. The extraction yields varied, with aqueous ethanol showing the highest yield (14.63%), followed by ethyl acetate (13.74%), ethanol (13.24%), and hexane (9.37%), reflecting solvent polarity's role in extraction efficiency. Phytochemical analysis revealed that ethanol and aqueous ethanol extracts were rich in flavonoids, tannins, phenolics, alkaloids, and glycosides, while hexane and ethyl acetate extracts contained terpenoids and steroids. The aqueous ethanol extract exhibited the highest total phenolic content (92.82 ± 1.89 mg GAE/g) and flavonoid content (86.91 ± 2.23 mg RE/g), correlating with strong antioxidant and anti-inflammatory potential. In COX inhibition assays, aqueous ethanol extract showed the strongest inhibition of COX-1 (IC₅₀ of 34.57 µg/mL) and COX-2 (IC₅₀ of 31.38 µg/mL), with flavonoids and phenolics primarily responsible for enzyme inhibition. These findings suggest that Leptadenia reticulata, particularly its aqueous ethanol extract, has substantial therapeutic potential as a natural anti-inflammatory agent, with selective COX-2 inhibition offering advantages in minimizing gastrointestinal toxicity. The study supports the plant's traditional use in managing inflammation and highlights its potential for further pharmacological and clinical exploration.