Parkinson's disease (PD) is characterized by a progressive and selective loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although the etiology of PD remains unclear, neuroinflammation has been implicated in the development of PD. Running exercise (Ex) promotes neuronal survival and facilitates the recovery of brain functions after injury. Therefore, we hypothesize that Ex protects the DA neurons against inflammation-induced injury in the SN. An intraperitoneal lipopolysaccharide (LPS, 1 mg/kg) injection induced microglia activation in the SN within hours, followed by a reduction in the number of DA neurons. LPS reduced the level of dopamine in the striatum and impaired the performance of motor coordination. Furthermore, the levels of the brain-derived neurotrophic factor (BDNF) were reduced in the SN by the LPS treatment. Four weeks of Ex before LPS treatment completely prevented the LPS-induced loss of DA neurons, reduction of dopamine levels and dysfunction of motor movement. Ex did not change the LPS-induced status of microglia activation or the levels of cytokines/chemokines, but restored the levels of LPS-reduced BDNF-TrkB signaling molecules. Blocking the action of BDNF, through its receptor TrkB antagonist, abolished the Ex-induced protection against LPS-induced DA neuron loss. Intrastriatal perfusion of BDNF alone was sufficient to counteract the LPS-induced DA neuron loss. Altogether, our results show that Ex protects DA neurons against inflammation-induced insults. The neuroprotective effects of Ex are not due to the modulation of inflammation status, but rather to the activation of the BDNF-TrkB signaling pathway.