Gouty arthritis (GA) is an inflammatory disease owing to the accumulation of monosodium urate (MSU) in joints, leading to redness and burning pain. In this study, the effect of Zisheng Shenqi Decoction (ZSD) on a rat model of MSU-induced GA was investigated. ZSD obviously diminished the right paw thickness, the degree of the swelling of the paw, and the infiltration of the inflammatory cell, as well as cartilage erosion, and widened the joint space in MSU-treated rats. Besides, MSU remarkably elevated the release of tumor necrosis factor- (TNF-), interleukin-1 (IL-1), IL-6, and IL-18; however, ZSD treatment dose dependently lowered these levels and resulted in a significant decrease in articular elastase activity. Also, ZSD administration increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) but declined malondialdehyde (MDA) and nitrogen monoxide (NO) contents. Importantly, western blotting analysis revealed that NOD-like receptor protein 3 (NLRP3), cleaved caspase-1, IL-1, nuclear factor-E2-related factor 2 (Nrf2) in the cytoplasm, phosphorylated mammalian target of rapamyclin (p-mTOR), and p62 expressions were downregulated, whereas the levels of nuclear Nrf2, phosphorylated AMP-activated protein kinase (p-AMPK), Beclin-1, and LC3II/I were upregulated by ZSD. Immunofluorescence assay indicated that ZSD evidently promoted nuclear translocation of LC3. Taken together, ZSD inhibited inflammation and oxidative stress and facilitated autophagy through the activation of the AMPK pathway and suppression of the mTOR signaling pathway, demonstrating its potential for preventing and curing GA.