Chronic cerebral ischemia (CCI) induced hyperphosphorylated Tau has been associated with an increased risk of neurodegenerative disorders such as Alzheimer’s and vascular dementia. This study investigated the neuroprotective effects of Antroquinonol (AQ), an ubiquinone derivative from Antrodia camphorata with anti-inflammatory and antioxidant properties. Bilateral internal carotid artery ligation (BICAL) in male Wistar rats and mixed rat primary neuron/glia co-cultures exposed to a hypoxia and hypoglycemia (HH) environment were used as experimental CCI models to investigate the therapeutic effects and mechanisms of AQ. AQ was administered daily at low or high doses for 28 days after BICAL induction. Two and four weeks after BICAL surgery, the functional and cognitive outcomes were evaluated by rotarod test, open field test (OFT), novel object recognition (NOR) and Y-maze test. Nissl, TUNEL, IHC and ICC staining, and Western blot analysis were used to evaluate the effects and underlying mechanisms of AQ in the treatment of CCI. The results showed that both low and high doses of AQ treatment significantly ameliorated motor deficits, anxiety-like behavior, and cognitive impairments in BICAL rats at 2 or 4 weeks post-CCI. Histological and molecular analyses revealed that AQ reduced neuronal injury, microglia activation, apoptosis, and Tau hyperphosphorylation in the cortex and hippocampus regions. We also found that AQ inhibited HH-induced hyperphosphorylation of Tau by modulating protein kinases (p-GSK3β Y216 and p-mTOR), LC3II, and p-NRF2 proteins in cultured cells, suggesting roles in kinase regulation, autophagy, and antioxidation. These findings support AQ as a promise therapeutic candidate for treating CCI-related neurodegenerative disorders.