Liver injury occurs frequently during sepsis. Pterostilbene (Pte), a natural dimethylated analog of resveratrol from blueberries, exerts anti-inflammatory and anti-apoptotic effects in various diseases. However, the role of Pte in sepsis-induced liver injury and its underlying mechanisms remain unknown. The current study aimed to evaluate the protective effects of Pte on sepsis-induced liver injury and its potential mechanisms. Sepsis was induced using cecal ligation and puncture (CLP) in C57BL/6 mice. Mice were administered Pte (5, 10, 15 mg/kg, i.p.) at 0.5 h, 2 h, and 8 h after CLP induction. The pathological changes of the liver were evaluated using hematoxylin and eosin (H&E) staining. The serum levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured. The levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL-6), myeloperoxidase (MPO), p38 mitogen-activated protein kinase (p38MAPK), Bax, and B-cell lymphoma 2 (Bcl-2) were also evaluated. Pte treatment attenuated the CLP-induced liver injury, as evidenced by the attenuated histopathologic injuries and the decreased serum aminotransferase levels. Pte reduced the serum inflammatory cytokine (TNF-α and IL-6) levels and hepatic mRNA levels of TNF-α and IL-6. Pte also reduced MPO activity and p38MAPK activation in the liver. Additionally, Pte significantly inhibited Bax expression and increased Bcl-2 expression. Moreover, Pte increased the expression of sirtuin-1 (SIRT1) and reduced the expression of acetylated forkhead box O1 (Ac-FoxO1), acetylated Ac-p53, and acetylated nuclear factor-kappa beta (Ac-NF-κB). However, SIRT1 small interfering RNA (siRNA) abolished Pte's effects on the expression levels of those protein. Notably, Pte improved the survival rate in septic mice. In conclusion, Pte alleviates sepsis-induced liver injury by reducing inflammatory response and inhibiting hepatic apoptosis, and the potential mechanism is associated with SIRT1 signaling activation.