The nuclear factor of activated T-cells (NFAT) family was first recognised to play an important role in the differentiation of T cells, but has since been shown to regulate multiple pathophysiological processes. However, whether it is involved in the pathogenesis of non-alcoholic steatohepatitis (NASH) remains unknown. Hepatic NFATc expression and localisation were analysed in C57BL/6 mice on a methionine–choline-deficient diet, as well as in samples from non-alcoholic fatty liver disease patients. Gain- or loss-of-function approaches were used to investigate the role of NFATc4 in NASH. NFATc4 translocates from the cytoplasm to the nucleus in hepatocytes of both humans and rodents with NASH. NFATc4 knockdown resulted in decreased hepatic steatosis, inflammation, and fibrosis during NASH progression. Mechanistically, we found that activated NFATc4 directly bound to peroxisome proliferator-activated receptor α (PPARα) in the nucleus and negatively regulated its transcriptional activity, thereby impairing the hepatic fatty acid oxidation pathway and increasing lipid deposition in the liver. Moreover, NFATc4 activation increased the production and secretion of osteopontin (OPN) from hepatocytes, which subsequently enhanced the macrophage-mediated inflammatory response and hepatic stellate cell-mediated fibrosis progression via paracrine signalling. Hepatic NFATc4 activation accelerates the progression of NASH by suppressing PPARα signalling and increasing OPN expression. Genetic or pharmacological inhibition of NFATc4 may have potential for future therapy of NASH. NFATc4 is activated in the non-alcoholic steatohepatitis of mice and patients. Inhibition of NFATc4 activation alleviates lipid deposition, inflammatory response, and fibrosis progression in the liver. Display omitted •NFATc4 is activated in the non-alcoholic steatohepatitis of mice and patients.•NFATc4 directly binds to PPARα and negatively regulates its transcriptional activity.•NFATc4 activation increases the production of OPN, which subsequently promotes hepatic inflammation and fibrosis via paracrine signalling.•Inhibition of NFATc4 alleviates the progression of non-alcoholic steatohepatitis.