Neuroinflammatory responses induced by accumulation and aggregation of β-amyloid (Aβ) peptide are mainly involved in Alzheimer's disease (AD) pathogenesis. Z-ligustilide (LIG), a novel neuroprotectant against ischemic stroke, was reported to have significant anti-inflammatory effects via inhibition of TNF-α production and bioactivity. The present study investigated the effect of LIG on AD-like cognitive impairment and neuropathological and neuroinflammatory changes induced by bilateral intracerebroventricular injections of Aβ25–35 at a dose of 50 nmol/rat. Rats received oral administration of 40 mg/kg LIG or volume-matched vehicle 1 h before Aβ25–35 treatment then once daily for 15 days. Morris water maze was used to detect the cognitive dysfunction induced by Aβ25–35. Compared to the sham-operated rats, Aβ25–35 injection significantly prolonged the mean escape latency in vehicle-treated rats in the Morris water maze test (p < 0.01) and increased both AD-related neuropathological signs (i.e., Aβ, amyloid precursor protein, and phosphorylated Tau immunoreactivity) and pro-inflammatory mediators (i.e., TNF-α and activated NF-kB) in the prefrontal cortex and CA1 subregion of the hippocampus. And these neurotoxic effects of Aβ25–35 were significantly ameliorated with LIG treatment (p < 0.01 vs. vehicle-treated group). The present data suggest that LIG modulates TNF-α-activated NF-kB signaling pathway with respect to its protective effect against Aβ25–35-induced neurotoxicity. LIG would be a potential candidate for further preclinical study aimed at the prevention and treatment of cognitive deficits in AD.