Understanding the relationship between dietary fat and physiological responses is crucial in species adapted to arid environments where water scarcity is common. In this study, we present a comprehensive exploration of gene expression across five tissues (kidney, liver, lung, gastrointestinal tract and hypothalamus) and 17 phenotypic measurements, investigating the effects of dietary fat in the desert-adapted cactus mouse (Peromyscus eremicus). We show impacts on immune function, circadian gene regulation and mitochondrial function for mice fed a lower-fat diet compared with mice fed a higher-fat diet. In arid environments with severe water scarcity, even subtle changes in organismal health and water balance can affect physical performance, potentially impacting survival and reproductive success. This study sheds light on the complex interplay between diet, physiological processes and environmental adaptation, providing valuable insights into the multifaceted impacts of dietary choices on organismal well-being and adaptation strategies in arid habitats.