To explore the mechanism by which zinc-α2-glycoprotein (ZAG) forms a feedback loop with extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) to regulate renal epithelial-mesenchymal transition (EMT) in renal tissue of hyperuricemia-induced renal fibrosis rats, 64 SPF-grade male Wistar rats were divided into a normal group and a hyperuricemia group. Half of the rats in each group were subjected to ZAG overexpression treatment to observe the interaction between ZAG expression levels and ERK1/2 and p38 MAPK signaling pathways in renal tissue. The results showed that compared with the normal group, the mRNA and protein levels of EMT-related molecules in the renal tissue of the hyperuricemia group were significantly upregulated. In the hyperuricemia group, ZAG overexpression reduced the serum uric acid (SUA) level, alleviated renal dysfunction, and delayed the progression of renal fibrosis in hyperuricemic nephropathy rats. Meanwhile, ZAG overexpression significantly decreased the expression of related proteins and their mRNA in the mitogen-activated protein kinase (MAPK) pathway in the renal tissue of hyperuricemic nephropathy rats. The findings indicate that ZAG overexpression inhibits the activation of ERK1/2 and p38 MAPK signaling pathways and delays the process of EMT, thereby alleviating renal injury and fibrosis caused by hyperuricemia and reducing hyperuricemic nephropathy in rats. These results open up a new research prospect for the potential preventive effect of ZAG on hyperuricemic nephropathy.