Milk proteins decrease food intake, body weight, and improve glycemic control; however, little is known about the underlying mechanisms of improvements in energy balance and glucose metabolism. The objectives of this study were to determine the effects of dietary whey, casein, and a combination of the 2, on food intake, energy expenditure, body composition, gut hormones, glucose tolerance, metabolic markers, and taste preference in diet-induced obese rats. In experiment 1, obese rats were randomly assigned to isocaloric high-fat diets (n = 12/group; 33% calories from fat) containing egg white (control; 14% protein calories), whey (WH; 40% protein calories), casein (CA; 40% protein calories) or whey + casein (WHCA; 40% protein calories). Measurements included various behavioral and metabolic parameters. In experiment 2, following an 8-d training period, preference for WH, CA, WHCA or control diets was assessed on consecutive days. Data were analyzed by MIXED procedure. WH, CA and WHCA decreased food intake, body weight and fat content with WH and CA producing pronounced effects. The hypophagic effects of WH were likely due to reduced dietary preference. WH and CA but not WHCA improved glucose tolerance, with WH being more effective. WH reduced energy expenditure at early stages, whereas CA and WHCA increased energy expenditure at later stages of the study. WH, CA and WHCA decreased plasma leptin, glucose-dependent insulinotropic polypeptide and interleukin-6, whereas WH increased glucagon-like peptide-1 concentrations. The CA and WHCA diets increased plasma membrane glucose transporter-4 (GLUT4) to total GLUT4 ratio in skeletal muscle; protein abundance of other markers of glucose and energy metabolism (total Akt, AMPKα, COX-IV, HADH, SIRT3) in the adipose and cardiac tissues did not differ. Overall, our data demonstrate that dietary whey, casein, and their combination, improve energy balance through divergent effects on food intake, energy expenditure, glucose tolerance and gut hormone secretion, with whey being more efficacious. These findings have potential significance for developing whey-based functional foods and nutraceuticals for weight and diabetic control.