Chronic graft-versus-host disease (cGvHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. The molecular mechanisms underlying cGvHD remain poorly understood and targeted therapies are not well established for clinical use. Here, we examined the role of the canonical WNT pathway in sclerodermatous cGvHD (sclGvHD). WNT signaling was activated in human sclGvHD with increased nuclear accumulation of the transcription factor β-catenin and WNT-biased gene expression signature in lesional skin. Treatment with highly selective tankryase inhibitor G007-LK, CK1α agonist pyrvinium or LRP6 inhibitor salinomycin, abrogated the activation of WNT signaling and protected against experimental cGvHD, without significant impact on graft-versus-leukemia effect (GvL). Treatment with G007-LK, pyrvinium or salinomycin almost completely prevented the development of clinical and histological features in the B10.D2 (H-2d)→BALB/c (H-2d) and in the LP/J (H-2b)→C57BL/6 (H-2b) model of sclGvHD. Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect, inflammation-dependent effects in sclGvHD. Our findings may have direct translational potential, as pyrvinium is in clinical use and tankyrase inhibitors are in clinical trials for other implications.