Formation of 5-hydroxymethyl furfural (HMF) and acetic acid, browning index (BI) and conformational changes in protein structure in infant formula (IF) powders were studied during storage at 25 and 45 °C and relative humidity (RH) range of 11–65%. Three powders with nutritional composition representing stages 1 (IF1), 2 (IF2) and 3 (IF3) of IF were studied. HMF formation in IF powders increased with increasing storage temperature and RH; the increase was highest in IF3 samples. BI showed a linear correlation with HMF concentration, irrespective of variation in product composition. Reduction in pH during storage could be associated with acetic acid formation as a result of Maillard reactions; these were also the likely cause of changes in protein conformation during storage, with decreases in α-helical structure and increases in β-sheets and β-turns observed. Overall, variation in levels of macro-nutrients influenced the degree of change in the commercial IF powders.