Updated project metadata. Many diseases, such as obesity, have systemic effects that impact multiple organ systems throughout the body. However, tools for comprehensive, high-resolution analysis of disease-associated changes at the whole-body scale have been lacking. Here, we developed a suite of deep learning-based image analysis algorithms (MouseMapper) and integrated it with tissue clearing and light sheet microscopy to enable a comprehensive quantitative analysis of diseases impacting diverse systems across the mouse body. This technological approach enables quantitative analysis of cellular and structural changes across the entire mouse body at unprecedented resolution and scale, including tracking nerves over several centimeters in whole animal bodies. To demonstrate its power, we applied MouseMapper to study nervous and immune systems in chow and high-fat diet (HFD)-induced obese mice. We uncovered widespread changes in both immune cell distribution and nerve structures, including alterations in the trigeminal nerve characterized by reduced nerve endings in obese mice. These structural abnormalities were associated with functional deficits of whiskers that they innervate and proteomic changes in their ganglion, primarily affecting pathways related to axon growth, and the complement system. Additionally, we revealed whole-body inflammation, which showed heterogeneity across different tissues in obese mice. Our study demonstrates MouseMapper's capability to discover and quantify pathological alterations at the whole-body level, offering a powerful new approach for investigating the systemic impacts of various diseases.