Abstract: Objective To investigate the effects of histone deacetylase 11 (HDAC11) on the learning and memory of rats after cerebral ischemia/reperfusion (I/R). Methods Adult male SD rats were randomly divided into four groups: a sham group, an modeling (I/R) group, a treatment (MGCD) group and a solvent control (PEG) group. A cerebral I/R model of rats was established by the four-vessel occlusion method. Rats in the sham group were occluded at the bilateral arteries without ligation of the carotid. The MGCD group was intracerebroventricularly injected with 50 μg/kg of MGCD0103 for 1 week before modeling. The PEG group was treated with PEG in the same way with the MBDC group. Morris water maze was performed for 5 days after reperfusion to observe the difference in learning and memory among the groups. Results From Days 2 to 5 after reperfusion, the I/R group showed longer latency than the Sham group (P<0.05). Meanwhile, compared with the I/R group, the MGCD group presented remarkably reduced escape latency (P<0.05). On Day 5 after reperfusion, rats were released into the pool without a platform. The percentages of the distance rats swam in the fourth quadrants divided by the distance rats swam in all quadrants were calculated, where the I/R group produced a lower percentage than the Sham group (P<0.05), but the MGCD group produced a higher percentage than the I/R group (P<0.05). Conclusions HDAC11 Inhibitor can relieve the damage of learning and memory in rats after cerebral I/R. HDAC11 may mediate the damage of learning and memory induced by cerebral I/R.