A composite face-centered experimental design was used to investigate the influence of spray drying conditions on the physicochemical characteristics of camel and cow milk powders. Response surface methodology (RSM) was deployed to appraise the effects of these processing parameters (the outlet drying temperature and the milk fat content) on water activity (a w), glass transition temperature (T g), bulk density, and free fat quantity. According to RSM analysis, it was noticed that the a w and the T g were primarily influenced by the outlet drying temperature instead of by milk fat content. Our results highlighted the negative effects of milk fat content and of the outlet drying temperature on the bulk density as well as on the free fat quantity of camel milk powder. Likewise, our findings underlined the negative effect of the outlet drying temperature on the bulk density of cow milk powder. However, the increase of fat content has led to the overexposure of fat at the free surface of the cow milk powder. Our results suggested a marked similarity of the overall thermodynamic behavior of both milks, during drying. Nevertheless, some differences were highlighted regarding the structuring of the particles of camel milk powder.