Arsenic, a ubiquitous environmental toxicant, has been implicated in causing liver fibrosis through chronic exposure. Histone lactylation is involved in various inflammatory diseases, among which liver fibrosis is included, and is also closely related to the regulation of immune cells. This work focuses on the mechanisms of histone lactylation and Th17 cell differentiation in arsenite-induced liver fibrosis through animal and cellular experiments. Chronic arsenite exposure of mice led to liver fibrosis, elevated glycolysis in liver, and increased lactate levels in both serum and liver, which promoted Th17 cell differentiation of CD4 T cells and increased IL-17A secretion. Treatment with oxamate, a lactate dehydrogenase inhibitor, suppressed Th17 cell differentiation and alleviated fibrosis in the liver. For HepG2 cells, arsenite exposure enhanced glycolysis and lactate levels, leading to increased global lactylation (Kla), H3K18la, interferon-regulatory factor 4 (IRF4), retinoic acid receptor-related orphan receptor gamma t (RORγt), and IL-17A expression and secretion in co-cultured Jurkat cells. Furthermore, in Jurkat cells, reducing lactate production and transport decreased these protein levels, suppressed Th17 cell differentiation, decreased IL-17A secretion, and ultimately inhibited the activation of hepatic stellate cells (HSCs). These results indicate that lactate derived from hepatocytes promotes Th17 cell differentiation by upregulating IRF4 through H3K18la, thereby enhancing IL-17A secretion and the activation of HSCs, contributing to arsenite-induced liver fibrosis. Our work reveals a new mechanism of histone lactylation in arsenite-induced liver fibrosis and offers a fresh perspective for the development of strategies for prevention and treatment of this condition.