Our recent study has revealed that moderate exercise upregulates the levels of miR-126 in circulating endothelial progenitor cell-derived exosomes (EPC-EXs), accompanying with enhanced protective function on endothelial cells. Whether exercise can regulate the function of circulating EPC-EXs on protecting neurons against hypoxia/reoxygenation (H/R) injury remains unclear. Here, we isolated the circulating EPC-EXs from exercise mice (10 m/min) and investigated their role in neurons subjected to H/R. EPC-EXs were characterized by nanoparticle tracking and western blot analyses. Mouse neurons (N2a) cultured in hypoxia condition for 6 hr followed by 24 hr reoxygenation. The H/R-injured N2a cells were treated with EPC-EXs (4 x 107 EPC-EXs/ml) isolated from exercise (EPC-EXsE) or sedentary mice (EPC-EXss). For mechanism study, N2a cells were transfected with miR-126 inhibitor or pre-treated with PI3k inhibitor (LY294002) for 2 hr. After 24 hr treatment, apoptosis and axon growth ability of N2a cells were determined. The growth factors (vascular endothelial growth factor/VEGF and brain derived neurotrophic factor/BDNF), miR-126 level and its downstream signal genes (PI3k and Akt) were measured. Our data showed that: 1) H/R insult induced decrease of VEGF and BDNF secretion as well as axon growth ability, increase of apoptosis of N2a cells; 2) EPC-EXS treatment raised miR-126 level and rescued N2a cells from H/R-induced injury, with better effect elicited by EPC-EXsE. 3) EPC-EXsE had better effect than EPC-EXS on activating the PI3k/Akt signal pathway, which was significantly reduced by miR-126 and PI3k inhibitors. Altogether, exercise boosts the effects of EPC-EXs on protecting neurons against H/R insult through activating the miR-126/PI3k/Akt signal pathway.