Systemic sclerosis (SSc) is a multi-organ fibrotic disease with few treatment options. Activated fibroblasts are the key effector cells in SSc responsible for the excessive production of collagen and the development of fibrosis. Platelet-derived growth factor (PDGF), a potent mitogen for cells of mesenchymal origin, has been implicated in the activation of SSc fibroblasts. Our aim was to examine the therapeutic potential of crenolanib, an inhibitor of PDGF receptor signaling, in cultured fibroblasts and in angiotensin II-induced skin and heart fibrosis. Crenolanib effectively inhibited proliferation and migration of SSc and healthy control fibroblasts and attenuated basal and transforming growth factor-β–induced expression of CCN2/CTGF and periostin. In contrast to healthy control fibroblasts, SSc fibroblasts proliferated in response to PDGFAA, whereas a combination of PDGFAA and CCN2 was required to elicit a similar response in healthy control fibroblasts. PDGF receptor α mRNA correlated with CCN2 and other fibrotic markers in the skin of SSc patients. In mice challenged with angiotensin II, PDGF receptor α-positive cells were increased in the skin and heart. These PDGF receptor α-positive cells co-localized with PDGF receptor β, procollagen, and periostin. Treatment with crenolanib attenuated the skin and heart fibrosis. Our data indicate that inhibition of PDGF signaling presents an attractive therapeutic approach for SSc.