Introduction: Long non-coding RNA (LncRNA) plays a critical role in cerebral ischemia-reperfusion (CI/R) injury. The purpose of the current research was to investigate the regulatory role of the LncRNA human leukocyte antigen complex group 11 (HCG11) in CI/R injury and explore its potential mechanism.Material and methods: The rat middle cerebral artery occlusion (MCAO) model was established to simulate CI/R injury in vivo. mRNA levels of HCG11, microRNA (miR)-381-3p, tumour protein p53, and neuro-inflammatory factors were detected by quantitative reverse transcription PCR (RT-qPCR). Bederson score and Longa score were assessed for neurological defi-cits. Triphenyl tetrazolium chloride (TTC) staining was used to examine the cerebral infarct volume. What is more, oxidative stress was evaluated by the commercial kit. Finally, the relationship between HCG11, miR-381-3p, and p53 was verified by a dual-luciferase reporter assay.Results: HCG11 was elevated in MCAO rats. And it competitively bound miR-381-3p and down-regulated the expres-sion of p53. Inhibition of HCG11 inhibited cerebral infarct volume and neurological deficits in MCAO rats, and inhibited the secretion of neuro-inflammation and the over-activation of oxidative stress, exerting the protective effect of CI/R injury. However, inhibition of miR-381-3p in rats significantly weakened the protective effect of depression of HCG11 in MCAO rats, resulting in increased cerebral infarction volume and neurological deficits, elevated neuro-inflammatory secretion, and oxidative stress activation.Conclusions: The present research shows that LncRNA HCG11 silencing protects against cerebral ischemia/reperfusion injury through miR-381-3p to regulate p53.