Objective To explore the protective effect of hydromorphone (HM) on cerebral ischemia reperfusion injury (CIRI) in rats and its effect on the expression of calmodulin‑dependent protein kinase kinase β (Ca MMKβ) and nuclear factor‑E2 related factor 2 (Nrf2)/heme oxygenase‑1 (HO‑1) signaling pathway . Methods According to the random number table method, 54 male SD rats were randomly divided into three groups (n=18): a sham operation (Sham) group, an ischemia reperfusion (IR) group, and a HM group (HM group). A cerebral CIRI model of rats was established in the IR group using the modified Longa thread plug method, while 5 mg/kg HM was injected into the HM group via the tail vein in addition to the treatment in the IR group. Those in the Sham group were treated without the thread plug (others were the same with the IR group). Then, the neurobehavioral scores of the three groups after recovery from anesthesia were recorded. The cerebral infarct area was measured. The content of reactive oxygen species (ROS), the concentration of malondialdehyde (MDA), the activity of superoxide dismutase (SOD) and the concentrations of tumor necrosis factor-α (TNF‑α) and interleukin (IL)‑1β in brain tissues were detected. The expression of Ca MMKβ was detected by immunohistochemical staining in paraffin‑embedded sections of the brain tissues. The relative expression of Nrf2 and HO‑1 proteins in brain tissues were detected by Western blot. Results Rats in the IR group and the HM group showed significantly higher neurobehavioral scores and cerebral infarct area percentage than those in the Sham group, while the neurobehavioral scores in the HM group were significantly lower than those in the IR group (P<0.05). Both the IR group and the HM group presented remarkable increases in ROS content, MDA concentration and the concentrations of TNF‑α and IL‑1β in brain tissue, compared with the Sham group, where the above indexes in the HM group were significantly lower than those in the IR group (P<0.05). Furthermore, both the IR group and the HM group showed remarkable decreases in SOD activity, the expression of Ca MMKβ and the relative expression of Nrf2 and HO‑1, compared with the Sham group, where the above indexes in the HM group were significantly higher than those in the IR group (P<0.05). Conclusions HM may inhibit oxidative stress and inflammatory response, and play a protective role in brain tissue by upregulating the expression of the Ca MMKβ and Nrf2/HO‑1 pathways in rats with CIRI.