A condition known as liver fibrosis, which refers to an excessive buildup of extracellular matrix (ECM) elements within the liver tissue, is regarded as a tissue repair or wound-healing state. If left untreated, this diseased stage can proceed to cirrhosis and eventually hepatocellular cancer. Here, we looked into the pharmacological effects and underlying mechanisms of Gardenia fructus (GF) against mice models with liver fibrosis caused by thioacetamide (TAA). GF reduced oxidation of hepatic tissue while also reducing inflammation in the liver. We further verified that GF caused ECM degradations, which alleviated liver fibrosis. We discovered the GF-regulated epigenetic regulator Sirtuin 1 (SIRT1) in the TAA-injected liver tissue, which provides insight into a potential underlying mechanism of GF. Strong support for these modifications was given by SIRT1-related signaling pathways, which were modulated by its downstream proteins, which included p47phox, AMP-activated protein kinase (AMPK), NADPH oxidase 2, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1, respectively. To verify the putative GF mechanism through cellular SIRT1 degradation, we used HepG2 cells under circumstances of chronic exposure and oxidative stress treated with hydrogen peroxide. In addition, GF dramatically decreased TGF-1-driven ECM accumulations in LX-2 cells that were dependent on SIRT1. All things considered, GF inhibited Nrf2 and AMPK/SIRT1 signaling pathways to inhibit liver fibrosis. Therefore, GF could eventually be employed to treat liver fibrosis in patients.