Zizania latifolia and its bioactive compound tricin have been recognized for their anti-inflammatory, anti-allergic, and anti-aging properties. However, the impact of Z. latifolia extract (ZLE) and tricin on astrocyte dysfunction, particularly related to disruptions in the amyloid β (Aβ) clearance pathway, has not been extensively studied. This research aims to explore the regulatory effects of ZLE and tricin on astroglial dysfunction, utilizing astrocytic differentiated C6 cells (passages 75~85) subjected to Aβ and high-dose insulin, as well as scopolamine-induced mice. Results revealed that ZLE (500 μg/ml) and tricin (1 μg/ml) significantly upregulated the expression of astrocyte proteins GFAP and AQP4, brain-derived neurotrophic factor (BDNF), low-density lipoprotein receptor-related protein 1 (LRP1), and matrix metalloproteinases (MMPs) in C6 cells treated with Aβ and high-dose insulin. Furthermore, oral administration of ZLE (100 and 300 mg/kg) and tricin (0.3 mg/kg) in mice led to an increase in acetylcholine (ACh) levels and upregulation of insulin-degrading enzyme (IDE), LRP1, and MMPs, while reducing the levels of acetylcholinesterase (AChE), Aβ and ApoE4. These findings suggest that ZLE and tricin may ameliorate Aβ and high-dose insulin-induced astrocyte dysfunction in C6 cells and scopolamine-treated mice, potentially through the AQP4/LRP1 pathway.