Hypoxia and ischemia cause neonatal encephalopathy and brain injury and can further result in cerebral palsy, cognitive impairment, growth restriction, and epilepsy. Induction of neuroprotection is a crucial therapeutic strategy for the treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). Hydrogen has neuroprotective effects against brain-related diseases. Inflammation and oxidative stress are the two main pathophysiological mechanisms in neonatal hypoxic-ischaemic injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an endogenous redox-sensitive transcription factor that participates in the antioxidant defence system through its effects on inflammation and oxidative stress. Herein, the research focuses on the mechanisms by which Nrf2 participates in the protection of hydrogen against HIE. The model of HIE was established by ligation of the right carotid artery and hypoxia in wild-type (WT) and Nrf2-/- mice. First, Nrf2 pathway activity was detected after hypoxia-ischaemia (HI) followed or not by hydrogen treatment. Brain injury, apoptosis, the inflammatory response, oxidative stress injury, and learning and memory function were assayed. We found that HI induced Nrf2 expression and signalling activation. Hydrogen alleviated the infarction volume, brain water content, neurological scores, apoptosis and long-term learning and memory functions after HI in WT mice but not in Nrf2-/- mice. Moreover, the oxidative products reactive oxygen species (ROS) and malondialdehyde (MDA) and the cytokines tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and High mobility group box 1 (HMGB1) were reduced and the antioxidant enzymes Superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) were upregulated by hydrogen treatment after HI in WT mice, but not in Nrf2-/- mice. In addition, the absence of Nrf2 abolished the suppressive effect of hydrogen on the expression of Nacht, Lrr, and Pyd domains-containing protein 3 (NLRP3) pathway members and p65 NF-κB after HI. Taken together, our findings showed that hydrogen alleviated cellular injury and apoptosis, neurobehavioural deficits, the inflammatory response and oxidative stress via the Nrf2-mediated NLRP3 and NF-κB pathways.