Objective To observe the effects of preconditioning with cinepazide maleate on the expressions of extracellular signal regulated kinases (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) of rats with cerebral ischemia and to explore the neuroprotective function of cinepazide maleate. Methods SD rats were randomly divided into the cinepazide maleate injection preconditioning operation group (treatment-operation group), normal saline injection preconditioning operation group (control-operation group), and cinepazide maleate injection preconditioning non-operation group (treatment-non-operation group). Each group had 30 rats and was preconditioned for 5 days. The cerebral ischemia models were established by occluding the left middle cerebral artery of rats in two operation groups through a modified suture method. At 8 h, 24 h, and 72 h after operations, brain tissues were taken out and their left side (ischemic side) and the corresponding right side were excised. The expressions and phosphorylation levels (the expressions of p-ERK1/2 and p-p38 MAPK) of ERK1/2 and p38 MAPK in both sides of brain tissues at each time point were detected by the Western blotting. Results The differences of relative expressions of total proteins of ERK1/2 and p38 MAPK in rat brain tissues from each group were not statistically significant (P>0.05). Compared to the treatment-non-operation group, the relative expressions of p-ERK1/2 protein in left side (operation side) of brain tissues of rats in the treatment-operation group and control-operation group at 8 h after operations were significantly up-regulated and were significantly down-regulated at 24 h and 72 h after operations. The differences were statistically significant (P<0.05). Also compared to the treatment-non-operation group, the relative expressions of p-p38 MAPK protein in left side (operation side) of brain tissues of rats in the treatment-operation group and control-operation group at 8 h, 24 h, and 72 h after operations were significantly up-regulated and the expressions of p-p38 MAPK protein of control-operation group was statistically higher than that of the treatment-operation group. The differences were statistically significant (P<0.05). Conclusion Cinepazide maleate may have protective effects at the early stage of cerebral ischemia.