Fatty liver disease is a growing problem in fish aquaculture and there is an urgent need to identify causes and possible remedies. In the present study, the effects of treating fatty liver disease in the Nile tilapia (Oreochromis niloticus Linnaeus, 1758) with an extract derived from a herb, Sedum sarmentosum Bunge (SSB), was investigated. We found that the SSB extract could restore the changes to feed coefficient, immune capacity, and pathological index caused by fatty liver disease, and also prevent apoptosis in hepatocytes. An RNA-seq analysis showed that treatment with SSB extract altered expression of genes in the lipid metabolic process, metabolic process, and oxidation-reduction process. Our results suggest that disorders of the PPAR and p53 signaling pathways may be involved in steatohepatitis development and in the therapeutic mechanism of the SSB extract treatment; these observations shed new light on possible treatment of steatohepatitis.