Type 2 diabetes (T2D) is a common chronic metabolic disease that poses a major challenge to global public health. Dysfunction of epididymal adipose tissue (eWAT) plays a pivotal role in the progression of T2D. However, the metabolic alterations occurring in eWAT under diabetic conditions remain incompletely understood. This study aims to comprehensively explore the metabolic changes in eWAT of db/db mice, a well-established model of T2D, by integrating untargeted metabolomics, targeted metabolomics, and lipidomics analysis. Our results reveal significant perturbations in the purine and histidine metabolic pathways. Specifically, we observed marked reductions in key metabolites, including adenosine monophosphate (AMP), xanthine, hypoxanthine, adenosine, and inosine, in the eWAT of db/db mice. Additionally, there were significant increases in short- and medium-chain acylcarnitines, along with elevated levels of short-chain fatty acids and tricarboxylic acid (TCA) cycle intermediates. Notably, distinct patterns of alterations in triglycerides, ceramides, and phosphatidylcholines were observed with each characterized by specific structural attributes. These results offer new perspectives on the metabolic reprogramming of eWAT in the diabetic state and identify potential targets for the development of therapeutic strategies.