Chrysanthemum zawadskii flower ethanol extract (CZ-F) was evaluated for its neuroprotective potential against inflammation-associated cognitive impairment. To assess its anti-inflammatory properties, we first conducted in vitro studies using LPS-stimulated BV2 microglial cells. CZ-F demonstrated strong antioxidant activity with IC₅₀ values of 186.04 µg/ml (DPPH) and 94.56 µg/ml (ABTS), suppressed the production of reactive oxygen species and nitric oxide, and downregulated the expression of iNOS and IL-1β, likely via inhibiting the NF-κB signaling pathway. CZ-F also decreased inflammation-induced acetylcholinesterase (AChE) expression and directly inhibited AChE activity. Among the constituents of CZF, quercetin and luteolin exhibited the strongest anti-inflammatory and antioxidant effects, while linarin most potently inhibited AChE activity. In an in vivo zebrafish model, CZ-F treatment ameliorated learning and memory impairments induced by sleep deprivation. These findings suggest that CZ-F can attenuate neuroinflammation and modulate cholinergic dysfunction, providing a potential therapeutic approach for inflammationrelated cognitive deficits.