TGF-β/Smad signaling pathway plays an important role in the pathogenesis and progression of liver fibrosis. Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+) dependent enzyme and responsible for deacetylating the proteins. Increasing numbers of reports have shown that the molecular mechanism of SIRT1 as an effective therapeutic target for liver fibrosis but the transformation is not very clear. In the present study, liver fibrotic tissues were screened by staining with Masson, hematoxylin-eosin staining (H&E) and Immunohistochemistry (IHC) for histopathological observation from the liver biopsy of seventy-seven rhesus monkey, which fixed with 4% paraformaldehyde (PFA) after treatment with high-fat diet (HFD) for two years. And the liver function was further determined by serum biochemical tests. The mRNA levels and protein expression of rat hepatic stellate (HSC-T6) cells were determined after treatment with Resveratrol (RSV) and Nicotinamide (NAM), respectively. The results showed that with the increasing of hepatic fibrosis in rhesus monkeys, the liver function impaired, and the transforming growth factor-β1 (TGF-β1), p-Smad3 (p-Smad3) and alpha-smooth muscle actin (α-SMA) was up-regulated, while SIRT1 and Smad7 were down-regulated. Moreover, when stimulated the HSC-T6 with RSV to activate SIRT1 for 6, 12, and 24 h, the results showed that RSV promoted the expression of smad7, while the expression of TGF-β1, p-Smad3 and α-SMA were inhibited. In contrast, when the cells stimulated with NAM to inhibit SIRT1 for 6, 12, and 24 h, the Smad7 expression was decreased, while TGF-β1, p-Smad3, and α-SMA expressions were increased. These results indicate that SIRT1 acts as an important protective factor for liver fibrosis, which may be attributed to inhibiting the signaling pathway of TGF-β/Smad in hepatic fibrosis of the rhesus monkey.