An autocrine driven upregulation of the Hedgehog (Hh) signaling pathway has been described in malignant pleural mesothelioma (MPM), in which the ligand, desert hedgehog (DHH), was produced from tumor cells. However, our investigation revealed that the Hh pathway is activated in both tumor and stroma of MPM tumor specimens and an orthotopic immunocompetent rat MPM model. This was demonstrated by positive immunohistochemical staining of Glioma associated oncogene 1 (GLI1) and Patched1 (PTCH1) in both tumor and stromal fractions. DHH was predominantly expressed in the tumor fractions. To further investigate the role of the Hh pathway in MPM stroma, we antagonized Hh signaling in the rat model of MPM using a Hh antagonist, vismodegib, (100 mg/kg peroral). Daily treatment with vismodegib efficiently downregulated Hh target genes, Gli1, Hedgehog Interacting Protein (Hhip) and Ptch1, and caused a significant reduction of tumor volume, and tumor growth delay. Immunohistochemical analyses revealed that vismodegib treatment primarily down regulated GLI1 and HHIP in the stromal compartment along with a reduced expression of previously described fibroblast Hh responsive genes such as Fibronectin (Fn1) and Vegf. Primary cells isolated from the rat model cultured in 3%O2 continued to express Dhh but did not respond to vismodegib in vitro. However, culture supernatant from these cells stimulated Gli1, Ptch1, and Fn1 expression in mouse embryonic fibroblasts which was suppressed by vismodegib. Our study provides new evidence regarding the role of Hh signaling in MPM stroma in the maintenance of tumor growth, emphasizing Hh signaling as a treatment target for MPM.