Background: This study investigates the neuroprotective effects of 1,8-cineole (1,8-CH), against hippocampal oxidative stress in a chronic unpredictable mild stress (CUMS) mice model of depression, focusing on the underlying molecular mechanisms. Methods: The effects of CUMS exposure were assessed by measuring oxidative stress markers, antioxidant activity, and neuronal damage in the hippocampus using histopathology, network pharmacology, Western blot analysis, and small interfering RNA (siRNA) knockdown experiments. Results: 1,8-CH significantly alleviated depression-like behaviors in CUMS mice. CUMS exposure induced oxidative stress in the hippocampus, evidenced by elevated MDA levels, decreased antioxidant activity, and neuronal damage. DHE staining revealed ROS accumulation. Treatment with 1,8-CH alleviated oxidative stress by reducing MDA, restoring antioxidant activity, and lowering ROS levels, while improving neuronal structure. Network pharmacology identified the PI3K/Akt/Nrf2 pathway as a key mediator of 1,8-CH’s neuroprotection, which was supported by Western blot results, demonstrating PI3K/Akt activation and a potential enhancement of Nrf2 nuclear translocation. Furthermore, in corticosterone-induced PC12 cells, the antioxidant effects of 1,8-CH were abolished by Nrf2 inhibition and siRNA knockdown, confirming Nrf2’s role. Conclusions: These findings suggest that 1,8-CH alleviates hippocampal oxidative stress in CUMS-induced depression via the PI3K/Akt/Nrf2 pathway, highlighting its potential as a health supplement for managing depression.