Pterostilbene (PTE) is broadly found in berries and has antioxidant and anti-inflammatory properties. To examine the effect of PTE on acute liver injury, mice were administrated PTE prior to concanavalin A (ConA). The mice were divided into the following groups: (i) vehicle control, (ii) ConA alone, (iii) ConA with PTE at 10 mg kg-1 (PTE low dose, PTL), and (iv) ConA with PTE at 40 mg kg-1 (PTE high dose, PTH). After the ConA challenge, the mice showed prompt induction of intrahepatic IFN-γ and TNF-α, followed by tissue factor (TF), which aggravated the fibrin deposition and massive liver necrosis. However, these effects were significantly counteracted by the PTE pretreatment. Furthermore, PTE reversed the phosphorylation of ConA-induced intrahepatic inflammatory kinases including JNK, ERK1/2, p38 and p65. Interestingly, PTE did not directly act on the hepatocytes, but inhibited intrahepatic macrophage accumulation and TF generation by inhibiting the activation of inflammatory p38 MAPK. These results suggest a promising avenue for the exploration of pterostilbene in improving acute liver injury.