Objectives: Obesity and diabetes are often associated with cardiometabolic diseases, despite there is substantial prognostic heterogeneity. We sought to identify circulating exosomal proteomic signatures of obesity with or without diabetes before and after bariatric surgery to provide insight into the biological pathways that contribute to the difference in response to bariatric surgery according to the presence of diabetes. Methods: Circulating exosomal proteins analyzed before and 6 months after bariatric surgery in 30 morbidly obese patients with (n = 12) or without (n = 18) diabetes were compared to those of 37 healthy volunteers. Results: Bariatric surgery induced weight loss and improvements in body mass index, fasting glucose, and urine protein levels in both groups, but white blood cell (p <0.001) and urine albumin (p <0.01) decreased only in non-diabetic obese patients. A total of 26 and 271 exosomal proteins were found to be significantly differentially expressed in diabetic obese patients compared to non-diabetic obese patients before and after bariatric surgery, respectively. Polymeric immunoglobulin receptors were downregulated, whereas inter-alpha-trypsin-inhibitor heavy chain 3 and adiponectin were upregulated in diabetic obesity after surgery. Glycoprotein 5, transthyretin, and immunoglobulin heavy constant gamma 1 were downregulated in non-diabetic obesity only. Proteins involved in innate and adaptive immunity shared the same trend, whereas glycosylphosphatidylinositol phospholipase D activity, lipid catabolic process, and vasoconstriction changed in the other direction following surgery. Conclusions: Diabetic obese patients have distinct exosomal protein signatures before and after bariatric surgery compared with non-diabetic obese patients. These novel exosomal proteins and associated pathways may provide insight into the mechanisms responsible for the progression of diabetes from obesity and, therefore, can be of significant therapeutic potential.