This proteomics dataset profiles hypothalamic extracellular vesicles (hEVs) during the early stages of diet-induced leptin resistance. Using next-generation proteomics in a discovery-driven approach, hEVs were analyzed from a hamster model subjected to a high-fat diet (HFD) for 30 days. The dataset captures alterations in hEV protein composition linked to disrupted cellular metabolism, neurodegeneration, and metabolic disorders, providing molecular evidence of early obesity-associated dysfunction.