Cardiovascular diseases are among the most common and serious health problems worldwide, and in Lebanon, their increase is closely linked to the adoption of a more westernized lifestyle. Given the potential risk of exposure to endemic Leishmania major, it was important to investigate whether the immune mechanisms underlying these two conditions might influence each other or alter clinical outcomes when they occur together. This study aimed to explore how a high-fat diet and Leishmania major infection interact to shape systemic immune responses in mice with different susceptibilities. C57BL/6 and BALB/c mice were selected for their predisposition to atherosclerosis (C57BL/6) or to Leishmania infection (BALB/c), as well as their distinct Th1/Th2 immune biases. We examined the combined effects of diet and infection on the morphological levels, even in the absence of female C57BL/6 mice for some comparisons. Immune responses were assessed at three different timepoints ( week 5, 10 and 15) by measuring Th1, Th2, and inflammatory cytokines in the plasma and key organs; spleen, paw skin, heart,and liver. C57BL/6 mice exhibited a strong Th1-driven response, reflecting their genetic background, while male BALB/c mice showed organ-specific mixed Th1/Th2 responses, with local Th2 signals predominating and systemic Th1 responses delayed. Female BALB/c mice on a high-fat diet displayed a diet induced pronounced Th2-immune response that was organ-specific. We also evaluated lipid deposition, atherosclerotic plaque formation, and hepatic metabolism markers such as CEACAM-1 and SREBP-1c. While the high-fat diet affected hepatic metabolism, BALB/c mice remained resistant to plaque formation. Overall, these findings elucidate that, although humans are naturally resistant to Leishmania major, they remain highly susceptible to diet-induced cardiovascular disease, which highlights the importance of preventive lifestyle measures.