The use of medicinal plants with favourable therapeutic effects has gained interest over conventional drugs in the treatment of oxidative stress and inflammatory-mediated diseases. The antioxidant and anti-inflammatory activities of Combretum paniculatum ethanolic extract (CPEE) were investigated in this study using in vitro and in vivo analysis. The results of phytochemical screening recorded in mg/100 g revealed that CPEE contains phenols (2711.02 ± 60.66), tannins (21.12 ± 0.41), flavonoids (49.00 ± 6.74), alkaloids (605.83 ± 10.10), steroids (0.64 ± 0.06), terpenoids (12.17 ± 0.55), reducing sugar (57.03 ± 0.12), and glycosides (2.59 ± 0.82). Our in vitro analysis revealed that CPEE inhibited nitric oxide, phospholipase A2, and thiobarbituric acid reactive substance activities with half-maximal inhibitory concentration (IC₅₀) values of 6.55, 361.1, and 2.28 µg/mL, respectively. Furthermore, the in vivo study showed that implantation of cotton pellets elicited an increase in granuloma tissue formation, levels of malondialdehyde (MDA), and C-reactive protein (CRP) while decreasing the activities of superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) in the untreated groups compared to normal rats. Interestingly, the groups treated with 100 and 200 mg/kg body weight of CPEE had decreased granuloma tissue, MDA, and CRP with an increase in the activities of SOD, CAT, and GSH. These findings suggest that CPEE ameliorated chronic inflammatory-induced oxidative stress in the experimental animals. Thus, it could be applied as an effective remedy for developing antioxidant and anti-inflammatory drugs.