Neuronal loss in cerebral ischemia primarily results from the combined effects of inflammatory responses and programmed cell death. Currently, there is an urgent need for potent neuroprotectants targeting both inflammatory and apoptotic responses for the treatment of ischemic stroke. Marine natural products are a vital source of novel drug candidates. Apo-9'-fucoxanthinone (APO-9'), a degradation product of fucoxanthin derived from marine brown algae, is known for its substantial anti-inflammatory effects, yet its neuroprotective action has not been clearly defined. In this study, the neuroprotective effects of APO-9' in alleviating cerebral ischemia injury and the underlying mechanism were primarily explored with the aid of tandem mass tag-based quantitative proteomics. APO-9' was found to markedly decrease the levels of inflammation factors by suppressing the IKK/IκB/NF-κB pathway in lipopolysaccharide (LPS)-induced BV2 cells. It also attenuated apoptotic responses in both LPS-induced BV2 cells and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced SH-SY5Y cells. These neuroprotective effects of APO-9' were linked to the activation of the PI3K/AKT pathway. Intraperitoneal injection of APO-9' in a MCAO mouse model showed significant cerebral protection against ischemia. The involvements of the IKK/IκB/NF-κB and PI3K/AKT/GSK-3β pathways were also confirmed in its alleviation of cerebral ischemia in vivo. This study established that APO-9' exerted neuroprotection against cerebral ischemia by inhibiting inflammatory and apoptotic cascades via the IKK/IκB/NF-κB and PI3K/AKT/GSK-3β signaling pathways.