Maladaptive repair after AKI may lead to progressive fibrosis and decline in kidney function. Sphingosine 1-phosphate has an important role in kidney injury and pleiotropic effects in fibrosis. We investigated the involvement of sphingosine kinase 1 and 2 (SphK1 and SphK2), which phosphorylate sphingosine to produce sphingosine 1-phosphate, in kidney fibrosis induced by folic acid (FA) or unilateral ischemia-reperfusion injury. Analysis of Masson trichrome staining and fibrotic marker protein and mRNA expression 14 days after AKI revealed that wild-type (WT) and Sphk1^–/– mice exhibited more kidney fibrosis than Sphk2^–/– mice. Furthermore, kidneys of FA-treated WT and Sphk1^–/– mice had greater immune cell infiltration and expression of fibrotic and inflammatory markers than kidneys of FA-treated Sphk2^–/– mice. In contrast, kidneys of Sphk2^–/– mice exhibited greater expression of Ifng and IFN-–responsive genes (Cxcl9 and Cxcl10) than kidneys of WT or Sphk1^–/– mice did at this time point. Splenic T cells from untreated Sphk2^–/– mice were hyperproliferative and produced more IFN- than did those of WT or Sphk1^–/– mice. IFN- blocking antibody administered to Sphk2^–/– mice or deletion of Ifng (Sphk2^–/–Ifng^–/– mice) blocked the protective effect of SphK2 deficiency in fibrosis. Moreover, adoptive transfer of Sphk2^–/– (but not Sphk2^–/–Ifng^–/–) CD4 T cells into WT mice blocked FA-induced fibrosis. Finally, a selective SphK2 inhibitor blocked FA-induced kidney fibrosis in WT mice. These studies demonstrate that SphK2 inhibition may serve as a novel therapeutic approach for attenuating kidney fibrosis.