Many therapeutic and nutritional benefits have been attributed to the different parts of Prosopis africana in numerous studies. This study investigated the effect of Prosopis africana leaf extract on inflammatory and oxidative stress markers in rats experimentally induced with obesity. Twenty Wistar albino rats (n = 5) were divided into a non-obese control group and three obese groups. The obese groups were first maintained on a high-fat diet for ten weeks before treatment. One of the obese groups served as the untreated control, while the remaining two groups were treated with 200 mg/kg and 400 mg/kg of the P. africana leaf extract (with return to normal diet), respectively. Serum TNF-α, IFN-γ, and MDA levels were measured after 28 days of treatment. The results showed that the untreated obese group had significantly (p < 0.05) elevated levels of TNF-α, IFN-γ, and MDA compared to the non-obese control. In contrast to the untreated obese group, the treatment groups exhibited significantly reduced levels of these parameters, with the most pronounced effect observed at the highest extract dose. This result highlights the potential therapeutic benefits of P. africana leaves in reducing obesity-related inflammatory processes, further supporting the health benefits that have been reported with the use of P. africana leaves.