Increasing evidence has shown that β‐amyloid (Aβ) induces hyperphosphorylation of tau and contributes to Aβ toxicity. Recently, tau hyperphosphorylation by glycogen synthase kinase‐3β (GSK‐3β) activation has been emphasized as one of the pathogenic mechanisms of Alzheimer's disease (AD). The phosphoinositide 3 kinase (PI3K)/Akt pathway is known as an upstream element of GSK‐3β. The inhibitory control of GSK‐3β, via the PI3K/Akt pathway, is an important mechanism of cell survival. In the present study, we investigated the neuroprotective effects of Angelica sinensis (AS), a traditional Chinese herbal medicine, against Aβ1–42 toxicity in cultured cortical neurons and also the potential involvement of PI3K/Akt/GSK‐3β signal pathway. We revealed that AS extract significantly attenuated Aβ1–42‐induced neurotoxicity and tau hyperphosphorylation at multiple AD‐related sites in a dose‐dependent manner. Simultaneously, it increased the levels of phospho‐Ser473‐Akt and down‐regulated GSK‐3β activity by PI3K activation. The neuroprotective effects of AS extract against Aβ1–42‐induced neurotoxicity and tau hyperphosphorylation were blocked by LY294002 (10 μM), a PI3K inhibitor. In addition, AS extract reversed the Aβ1–42‐induced decrease in phosphorylation cyclic AMP response element binding protein (CREB), which could be blocked by the PI3K inhibitor. These results suggest that AS‐mediated neuroprotection against Aβ toxicity is likely mediated by the PI3K/Akt/GSK‐3β signal pathway. © 2010 Wiley‐Liss, Inc.