Kindlin-2 is an adaptor protein that contributes to renal tubulointerstitial fibrosis (TIF). Epithelial-to-mesenchymal transition (EMT) in tubular epithelial cells was regarded as one of the key events in TIF. To determine whether Kindlin-2 is involved in the EMT process, we investigated its regulation on EMT in human kidney TECs and explored the underlying mechanism. In this study, we found that overexpression of Kindlin-2 suppressed epithelial marker E-cadherin and increased the expression of fibronectin and the myofibroblast marker α-SMA. Kindlin-2 significantly activated ERK1/2 and AKT and inhibition of ERK1/2 or AKT reversed Kindlin-2-induced EMT in human kidney TECs. Mechanistically, Kindlin-2 interacted with Ras and Sos-1. Furthermore, overexpression of Kindlin-2 increased Ras activation through recruiting Sos-1. Treatment with a Ras inhibitor markedly repressed Kindlin-2-induced ERK1/2 and AKT activation, leading to restraint of EMT. We further demonstrated that knockdown of Kindlin-2 inhibited EGF-induced Ras-Sos-1 interaction, resulting in reduction of Ras activation and suppression of EMT stimulated by EGF. Importantly, we found that depletion of Kindlin-2 significantly inhibited activation of ERK1/2 and AKT signaling in UUO mice. We conclude that Kindlin-2, through activating Ras and the downstream ERK1/2 and AKT signaling pathways, plays an important role in regulating renal tubular EMT and could be a potential therapeutic target for the treatment of fibrotic kidney diseases.