Cognitive impairment is one of the most common comorbidities in individuals suffering from neuropathic pain. However, the mechanisms underlying pain-associated cognitive dysfunction remain unclear. Studies show that IL-33 is essential for synaptic plasticity, which is necessary for learning and memory formation. Here, we used a spared nerve injury (SNI) model in mice to induce cognitive dysfunction associated with neuropathic pain. Behavioral changes following surgery were assessed using Von Frey test, open field test and novel object recognition test. Immunofluorescence, chemical genetics, and stereotaxic injections were employed to investigate the potential mechanisms. Mitochondrial morphology and oxidative stress levels were evaluated using transmission electron microscopy and by measuring the superoxide dismutase (SOD) activity and reactive oxygen species (ROS) production. The data suggest that animals after SNI with comorbid memory dysfunction exhibited a decline in IL-33 levels in the dorsal hippocampal CA3 region, accompanied by deactivated astrocytes. The expression of IL-33-positive astrocytes was reduced, and the number of dendritic spines was decreased. Additionally, SOD activity was decreased, ROS production increased, accompanied with impaired mitochondrial morphology in synapses. Exogenous IL-33 administration or enhancing endogenous IL-33 release via chemogenetic activation of astrocytes alleviated cognitive impairment. These effects were mediated by improvement in mitochondrial morphology, reduction in oxidative stress levels, and increase in the number of dendritic spines. Findings indicated that IL-33 derived from astrocytes in the dorsal CA3 contributes to synaptic plasticity and oxidative stress in SNI mice. Accordingly, IL-33 may serve as a potential therapeutic target for pain-associated cognitive impairment.