The objective of this study was to develop a mathematical model to predict the loss of available lysine and the formation of Maillard reaction (MR) compounds in sweet whey during spray drying process. The heat damage and other spray drying process-related variables were estimated with the compartment model coupled to the drying kinetics of droplets. The model was adequate to determine the outlet temperature of air and the final moisture content of the product. The model predicted available lysine losses like those found experimentally. However, the model predicted a higher furosine concentration than that found experimentally. The browning index exhibited no significant increase for experimental and calculated results during the spray drying, possibly because the MR did not reach the final stages. The model showed to be comparable to those reported in the literature, with the advantages of being computationally less time-consuming and providing confidence intervals for the response variables. Practical applications: This work presents the integration of several mathematical models to predict the loss of available lysine and the formation of some heat damage indicators during the spray drying of whey. The model contributes to the understanding of relevant variables—such as residence time distribution, global heat transfer coefficient of the dryer, thermal properties of the drying media, glass transition temperature, drying kinetics, drying air inlet, and outlet temperature among others—on the loss of food quality regarding the thermal process. This information could help the decision-making process that can lead to the optimization of spray drying to obtain food with minimal thermal damage and therefore the maximum amount of available nutrient content.