Abstract How regular physical activity is able to improve health remains poorly understood. The release of factors from skeletal muscle following exercise has been proposed as a possible mechanism mediating such systemic benefits. We describe a mechanism wherein skeletal muscle, in response to a hypertrophic stimulus induced by mechanical overload (MOV), released extracellular vesicles (EVs) containing muscle‐specific miR‐1 that were preferentially taken up by epidydimal white adipose tissue (eWAT). In eWAT, miR‐1 promoted adrenergic signaling and lipolysis by targeting Tfap2α , a known repressor of Adrβ3 expression. Inhibiting EV release prevented the MOV‐induced increase in eWAT miR‐1 abundance and expression of lipolytic genes. Resistance exercise decreased skeletal muscle miR‐1 expression with a concomitant increase in plasma EV miR‐1 abundance, suggesting a similar mechanism may be operative in humans. Altogether, these findings demonstrate that skeletal muscle promotes metabolic adaptations in adipose tissue in response to MOV via EV‐mediated delivery of miR‐1.