Objective Altering energy supply and the relative proportions of energy source in the first weeks of life of dairy calves may influence glycemic and insulinemic responses. The objective of this study was to assess the metabolic responses to high-lactose or high-fat milk replacer. Materials and Methods Forty male calves were fed 7 L of milk replacer per day in 2 meals given 10 h apart, considered either high lactose (44% lactose, HL) or high fat (37% lactose, HF), from the first week of life to 30 d of age. Postprandial blood plasma glucose, insulin, and acetaminophen (an abomasal emptying marker) concentrations were measured up to 420 min and used to fit a mathematical model of abomasal emptying and glucose–insulin dynamics. Additionally, an i.v. glucose tolerance test was used to assess glucose tolerance and insulin sensitivity. Results and Discussion Insulin sensitivity remained unchanged; however, glucose maximal concentration and change from baseline tended to be greater for HL in response to an i.v. glucose challenge. Postprandial glucose was elevated at 30 min for HL and HF at 60 and 90 min. Model parameterization showed no difference in abomasal emptying; however, intestinal glucose absorption tended to be faster with HL. Potentiation of insulin action was greater with HL, and pancreatic responsiveness tended to be greater with HF. Implications and Applications These results suggest HL increased early-phase postprandial glucose appearance, which may influence insulin action. In this study, modifying milk replacer composition to more closely resemble cow’s milk did not negatively affect glucose metabolism.