Kgenwge melon (Citrullus lanatus) is an indigenous food crop of sub-Saharan Africa and various other tropical countries, commonly utilized as food and/or snack. Current reports evidenced lower mortality rates due to coronary artery diseases in such nations. Only a few studies have demonstrated anti-inflammatory properties of the conventional watermelon consumption through improved lipid profile in humans and animal models. Therefore, the aim of this thesis was to explore the anti-atherogenic potential of Kgengwe seed powder (KSP) and its possible mechanisms of action to exhibit such effects in low-density lipoprotein receptor knockout (LDL-r-KO) mice fed with an atherogenic (0.06% (w/w) cholesterol) chow. Twenty male LDL-r-KO mice were divided into two groups; control (n=10, fed with atherogenic diet) and treated (n=10, fed with an atherogenic diet supplemented with 10% (w/w) KSP) for a period of 20 weeks. During the experimental course, animal body weight gain, food intake, and plasma lipid levels were measured and compared between both the experimental groups. Unlike the previous reports, the present study did not show any significant changes in the plasma lipid levels between the groups. However, KSP treated group showed a significant (p < 0.05) decrease of the atherosclerotic lesion size in the aortic roots as compared to that in the controls. Thus, the plasma samples of mice were further assessed to investigate any substantial alterations in the plasma cytokine levels, oxylipin profile, and plasma and fecal metabolites. The anti-atherogenic potential of KSP was attributed to significant (p < 0.05) and beneficial variations in the plasma inflammatory markers, oxylipins, plasma and fecal metabolites in KSP treated mice in comparison to controls. These preliminary set of data indicate the cardioprotective properties of this fruit’s seeds which are presumed to be mediated through changes in the inflammatory pathways.