Activation of the NogoA/NgR/ROCK pathway limits nerve repair after brain ischemia-reperfusion (I/R) injury. Triptolide displays anti-inflammatory, anti-oxidant, and immunosuppressive effects and is derived from the traditional Chinese medicine Tripterygium wilfordii Hook F. This agent can also penetrate the blood-brain barrier, where it has a neuroprotective effect and ameliorates cerebral I/R injury via an as yet unknown mechanism(s). Here, an animal model of middle cerebral artery occlusion and reperfusion (MCAO/R) was employed to assess triptolide’s therapeutic impact on brain I/R injury and the possible mechanism of action. The results indicate that triptolide treatment can decrease cerebral infarction and nerve injury after cerebral I/R injury. Importantly, in vivo and in vitro experiments revealed that treatment with triptolide decreased NogoA, NgR, p75NTR and ROCK2 expression, and upregulated the expression of GAP43 and PSD-95, thus suggesting improved synaptic function. These results indicate that triptolide can promote nerve repair following brain I/R injury by inhibiting NogoA/NgR/ROCK signalling.