Treatment of JAK2V617F driven myeloproliferative neoplasms (MPNs) with Ruxolitinib (JAK inhibitor, JAKi) has shown limited disease-modifying benefits and has led to the search for other pathways as potential therapeutic targets for this disease. We investigated the effects of Smoothened inhibition (SMOi) using the small-molecule inhibitor PF-04449913 (PF-13) in a JAK2V617F transgenic mouse model that recapitulates many of the phenotypes of MPNs including bone marrow fibrosis and splenomegaly. We show both that hedgehog (Hh) signaling pathway is activated in JAK2V617F cells and that SMOi reduces splenomegaly in JAK2V617F mice. In a murine bone marrow transplant model, we show that SMOi also reduces JAK2V617F allelic burden. JAK2V617F mice show increased pERK and NF-κB signaling, which is reduced with SMOi. Finally, we found that SMO inhibitor blocks bone marrow fibrosis by reducing TGF-β signaling. In conclusion, this report provides critical insight into the mechanism of action of SMO inhibitors in JAK2V617F associated MPN.