The onset of obesity is characterized by early physiological and molecular changes, including leptin resistance and hypothalamic dysfunction, preceding significant weight gain and metabolic complications. Extracellular vesicles (EVs) are key mediators of intercellular communication, reflecting early pathological shifts in metabolic disorders. This study investigates the role of hypothalamic EVs (hEVs) in early obesogenic insult and their potential implications for obesity-related comorbidities. Using a hamster model fed a high fat diet for 30 days, next-generation proteomics revealed altered hEV protein compositions linked to cellular metabolism, neuroinflammation, and metabolic dysfunction, mirroring early obesity-related dysfunction. These findings highlight the adaptive molecular profiles of hEVs during early obesogenic insult and their potential as biomarkers and molecular mediators in obesity progression and its comorbidities. In conclusion, this study provides new insights into the molecular mechanisms underlying the onset of obesity and highlights hEVs as promising targets for early detection and intervention.