A variety of inbred mouse strains have been used for research in metabolic disorders. Despite being inbred, they display large inter-individual variability for many traits like food intake and body weight. However, the relationship between dietary macronutrients and inter-individual variation in body weight and food intake of different mouse strains is still unclear. We investigated the association between macronutrient content of the diet and variations in food intake, body composition, and glucose tolerance by exposing five different mouse strains (C57BL/6, BALB/c, C3H, DBA/2, and FVB) to 24 different diets with variable protein, fat, and carbohydrate contents. We found only increasing dietary fat, but not protein or carbohydrate had a significant association (positive) with variation in both food intake and body weight. The highest variation in both body weight and food intake occurred with 50% dietary fat. However, there were no significant relationships between the variation in fat and lean mass with dietary protein, fat, or carbohydrate levels. In addition, none of the dietary macronutrients had significant impacts on the variation in glucose tolerance ability in C57BL/6 mice. In conclusion, the variations in food intake and body weight changes increased with the elevation of dietary fat levels.