In this study the combined effect of AMPK activator AICAR (500 mg/kg, SC) and PPARδ agonist GW501516 (5 mg/kg, IP) was studied on recovery of motor function in adult male mice after stroke. Vehicle or drug treatments were initiated 24 - 32 h after induction of stroke using the photothrombotic model and lasted until day 10 after stroke. In addition to pharmacological therapy, mice were allowed to voluntarily run on wheels in their home cage starting from day 7 after stroke. Motor function was assessed in grid walking and cylinder tests 3 days before and 1, 7, 14 and 21 days after stroke. On day 21 post-stroke, mouse brains were fixed by cardiac perfusion and collected for sectioning and evaluation of infarct volume in half of the experimental animals. In the second half of the experimental mice, brains were removed without fixation, the cerebral cortex involving the infarct core plus the peri-infarct region (~3mm total diameter) and the corresponding contralateral part of the cortex were excised and used for extraction and evaluation of proteins. The results of both sensorimotor tests indicated that voluntary running started 7 days post-stroke marginally facilitates motor recovery after stroke, whereas, addition of AICAR and GW501516 therapy (starting 1 day post-stroke) to running potentiates motor recovery. Interestingly, the average total distance run by mice receiving the drug therapy was less than that of the vehicle-treated group. Infarct volumes measured at day 21 post-stroke were comparable in both groups. Increased relative levels of BDNF and CpG-binding protein 2 (MECP2) were documented in the cerebral cortex of drug vs. vehicle-treated group. Our data indicate that pharmacological activation of AMPK and PPARδ following stroke enhances motor recovery offered by voluntary running, and that this effect is likely due to increased availability of BDNF and sustained activation of its downstream signaling pathways.