During storage, a series of changes occur for dairy powders, such as protein lactosylation and the formation of Maillard reaction products (MRPs), leading to powder browning and an increase of insoluble matter. The kinetics of protein lactosylation and MRP formation are influenced by the lactose content of the dairy powder. However, the influence of lactose in the formation of insoluble matter and its role in the underlying mechanisms is still a subject of speculation. In this study, we aim to investigate the role of lactose in the formation of insoluble matter in a more comprehensive way than the existing literature. For that, two casein powders with radically different lactose contents, standard micellar casein (MC) powder (MCI) and a lactose-free (less than 10 ppm) MC powder (MC2), were prepared and stored under controlled conditions for different periods of time. Powder browning index measurements and solubility tests on reconstituted powders were performed to study the evolution of the functional properties of MC powders during aging. Proteomic approaches [one-dimensional electrophoresis and liquid chromatography mass spectrometry (LC-MS)] and innovative label-free quantification methods were used to track and quantify the chemical modifications occurring during the storage of the powders. Reducing the amount of lactose limited the browning of MC powders but had no effect on the loss of solubility of proteins after storage, suggesting that the action of lactose, leading to the production of MRC, does not promotes the formation of insoluble matter. Electrophoresis analysis did not reveal any links between the formation of covalent bonds between caseins and loss in solubility, regardless of the lactose content. However, LC-MS analyses have shown that different levels of chemical modifications occur during the MC powder storage, depending upon the presence of lactose. An increase of protein lactosylation and acetylation was observed for the powder with a higher lactose content, while an increase of protein deamidation and dephosphorylation was observed for that containing lower lactose. The decrease of pH in the presence of lactose as a result of Maillard reaction (MR) may explain the difference in the chemical modifications of the two powders. In view of the present results, it is clear that lactose is not a key factor promoting insolubility and for the formation of cross-links between caseins during storage. This suggests that lactosylation is not the core reaction giving rise to loss in solubility.