AbstractCardiovascular disease (CVD) burden represents a major challenge for health care systems worldwide. Dyslipidemia is an important factor that triggers the atherogenic process and CVD development. The intake of legume seeds has been associated with a reduced risk of CVDs. Seed flour of Prosopis laevigata is a good source of protein, with high levels of active compounds. In the present work, the dyslipidemia‐prone C57BL/6J mouse was used to evaluate the potential of a diet based on mesquite seed to prevent CVD development, through the reduction of blood lipid levels. The diet based on mesquite seed (D1MS) supported the nutritional requirements of mice for the growing stage as the diet based on casein (D2Cas) and standard chow (D3SC). Mice treated with the diet D1MS (2.33%) had significantly lower visceral fat deposition than mice treated with the diet D2Cas (3.32%) and the diet D3SC (3.48%). Treatment with the diet D1MS decreases significantly the blood levels of glucose, triglycerides, and cholesterol, resulting in a lower atherogenic index than treatments with D2Cas and D3SC diets. The phenolic compound content and specifically the presence of apigenin in the diet D1MS decrease body fat accumulation and atherogenic index in C57BL/6J mouse model, suggesting an important anti‐atherogenic potential of mesquite seed.