Objective To explore the effects of enriched environment preconditioning on the expression of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) and apoptosis in the peri-infarct cortex of rats after cerebral ischemia-reperfusion. Methods A total of 45 male Sprague-Dawley rats were randomly divided into sham group, model group and enriched environment preconditioning group, with 15 rats in each group. Before modeling, rats in the sham group and model group were fed in standard environment cages, while rats in the enriched environment preconditioning group were fed in enriched environment cages, all for 3 weeks. The transient middle cerebral artery occlusion model was established by modified Longa's method in the model group and enriched environment preconditioning group, while rats in the sham group were not inserted with suture. Modified neurological severity score (mNSS) was used to evaluate the neurological function 1-3 d after operation. The brain tissue was harvested 3 d after the operation, the pathological changes of the peri-infarct cortex were observed by hematoxylin-eosin staining, the apoptosis was observed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL), the activation of microglia ionized calcium-binding adaptor molecule 1 (Iba-1) was observed by immunofluorescence, and the expression of TNF-α and IL-1β was detected by Western blotting. Results Compared with the sham group, the peri-infarct cortical tissue in the rats of model and enriched environment preconditioning groups had obvious pathological changes, and the mNSS, TUNEL positive cell number, the activation of microglia Iba-1, the expression of TNF-α and IL-1β were increased (all P<0.05). Compared with the model group, mNSS, TUNEL positive cell number, the activation of microglia Iba-1, and the expression of TNF-α and IL-1β were decreased in the enriched environment preconditioning group (all P<0.05) and the degree of peri-infarct cortical tissue injury was alleviated. Conclusion Enriched environment preconditioning can attenuate neurological function and peri-infarct brain tissue injuries in rats after cerebral ischemia-reperfusion, and the mechanism may be related to the inhibition of inflammation and apoptosis in the peri-infarct cortex.