It is well known that physical exercise is rewarding and protective against drug abuse and addiction. However, the neural mechanisms underlying these actions are not fully understood. In this report, we found that prolonged daily voluntary wheel-running produced a more robust increase in c-fos expression in the red nucleus (RN) than in other brain regions. Subsequent neuronal tracing imaging and electrophysiological assays demonstrated that most RN neurons are glutamatergic in its magnocellular portion (RNm) and wheel-running activates a subset of RNm glutamate neurons that project to the neighboring ventral tegmental area (VTA), particularly to contralateral VTA dopamine neurons. Selective stimulation of this pathway is rewarding, as assessed by optical intracranial self-stimulation (oICSS) and conditioned place preference (CPP), whereas optical inhibition of this pathway blocked wheel-running behavior, suggesting that the RN-to-VTA glutamate pathway, at least in part, underlies exercise reward. Furthermore, wheel-running or direct stimulation of this pathway inhibited cocaine self-administration and cocaine seeking during extinction, suggesting that this newly identified local circuit that links the motor circuitry and brain reward system at least in part underlies its therapeutic anti-cocaine effects. Together, these findings not only expand our understanding of how physical activity produces exercise reward but also help us understanding how regular physical exercise produces such a wide range of therapeutic benefits as anti-cocaine use, anti-depression, anti-anxiety, and anti-obesity.