Physical exercise affects multiple physiological processes, including those regulated by hormones, such as energy balance, stress responses, and pain perception. The prohormone precursor proopiomelanocortin (POMC) gives rise to β-endorphin, adrenocorticotropic hormone, β-lipotropin, and the melanocyte-stimulating hormones (MSH), which act through melanocortin (MC1-5) and opioid receptors to influence these key physiological responses. Here, we identified a mechanism by which full-length POMC interacts with small extracellular vesicles (sEVs) in the circulation. In healthy adults, the fraction of plasma POMC associated with sEVs increased fourfold following intense exercise, despite unchanged POMC and sEV concentrations. POMC-positive sEVs contained leukocyte or megakaryocyte/platelet markers, suggesting hematopoietic origin. A substantial subset of circulating sEVs expressed MC1–MC5 and μ-opioid receptors, and coimmunoisolation assays demonstrated binding of unprocessed POMC to MC1 and MC3 receptors. Molecular modeling indicated that POMC undergoes pH-dependent conformational changes that favor MC binding, a finding corroborated by in vitro binding assays under acidic conditions. Functionally, addition of POMC-positive sEVs to B16-F10 melanoma cells induced melanogenesis, consistent with POMC-derived MSH activity. The sEV-associated POMC had higher rates of transport than unbound POMC in assays mimicking the blood–brain barrier. These findings establish that exercise-induced, pH-dependent binding of POMC to circulating sEVs may facilitate hormone precursor transport and potentially influence transfer across the blood–brain barrier. This mechanism represents a separate paradigm for endocrine regulation, providing insight into how exercise modulates sEV interactions with systemic hormone distribution and signaling.