Whey protein is often reported to promote satiety, aid in weight loss and stimulate energy expenditure. However, there is limited information on the relative efficacies of the individual components of whey – lactalbumin and lactoferrin – on energy balance and diabetic control. Our objectives were to compare the effects of whey with lactalbumin and lactoferrin on weight, body composition, food intake, energy expenditure, glucose tolerance and meal-induced hormone responses in diet-induced obese (DIO) rats. The DIO rats were randomized to receive one of 3 isocaloric and isonitrogenous high-fat diets (n = 8/group; 40% calories from fat, 30% protein calories): (1) whey (WH), (2) lactalbumin (LA), or (3) lactoferrin (LF) and were followed for 65 d (d). Food intake, energy expenditure, body composition, glucose tolerance and plasma satiety hormone concentrations were measured. Data were analyzed by repeated measures ANOVA or ANCOVA. Compared with WH, LF decreased food intake, and decreased energy expenditure during the dark period for the first 14 d of treatment. LA did not alter food intake, but increased energy expenditure during the first 3 h of the dark period after ~34 d of treatment interventions. LF reduced body weight by reducing adipose mass after 7 d whereas LA did not alter body weight and composition. When food intake was used as a covariate, LF reduced blood glucose and plasma leptin, but neither LA nor LF altered plasma concentrations of satiety hormones (GLP-1, GIP, PYY, insulin, amylin). Though glucose tolerance did not differ between WH, LA and LF by 30 d, LA and LF improved glucose tolerance by 60 d. In summary, lactoferrin is more effective than whey in inducing hypophagia, promoting fat loss, improving glucose tolerance and in decreasing plasma leptin, whereas lactalbumin is effective in increasing energy expenditure and improving glucose tolerance. These components seem to be more beneficial than just whey itself in improving energy balance and glucose tolerance.