Expression of miR-137 is downregulated in brain tissue from patients with depression and suicidal behavior, and is also downregulated in peripheral blood from stroke patients. However, it is not yet known if miR-137 acts as a bridge between stroke and depression. To test this, we used middle cerebral artery occlusion and chronic mild stress to establish a post-stroke depression model in rats. Compared with controls, we found significantly lower miR-137 levels in the brain and peripheral blood from post-stroke depression rats. Injection of a miR-137 antagonist into the brain ventricles upregulated miR-137 levels, and improved behavioral changes in post-stroke depression rats. Lu-ciferase assays showed miR-137 bound to the 3′UTR of Grin2A, regulating Grin2A expression in a neuronal cel line. Grin2A gene overexpression in the brain of post-stroke depression rats, noticea-bly suppressed the inhibitory effect of miR-137 on post-stroke depression. Overal , our results show that miR-137 suppresses Grin2A protein expression through binding to Grin2A mRNA, thereby ex-erting an inhibitory effect on post-stroke depression. Our results offer a new therapeutic direction for post-stroke depression.