Idiopathic pulmonary fibrosis (IPF) is a lung disease with limited therapeutic options characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP/TAZ are transcriptional co-activators that mediate mechanical and biochemical signals controlling fibroblast activation. Given their central role in fibrogenesis, blocking fibroblast activation and differentiation is a promising therapeutic strategy for fibrotic diseases. Thus, we developed a high-throughput small molecule screen for YAP inhibitors in primary human lung fibroblasts (HLF) with the purpose of identifying new therapies for IPF. We screened 13,232 compounds in HLF and selected hits that decrease YAP nuclear/cytoplasmic ratio. Western blot, qPCR and immunofluorescent staining were used to analyze the effects of drug treatments, siRNA-mediated knockdown and media supplementation. The bleomycin mouse model was used to evaluate therapeutic drug efficacy. YAP localization in mouse fibroblasts in vivo was measured by imaging flow cytometry. We identified multiple statins (HMG-CoA reductase inhibitors) as YAP inhibitors in our primary screening. We confirmed cerivastatin, simvastatin and mevastatin elicit a dose-dependent decrease of nuclear YAP. We demonstrate statins increase the ratio of S127-phosphorylated YAP, characteristic of cytoplasmic retention. Moreover, we detected a marked increase in S397 phosphorylation, which marks YAP for proteasomal degradation. Consistently, treatment with the three statins reduced total YAP levels. We further link the mevalonate pathway, targeted by statins, to YAP regulation. Knockdown of HMGCS1, FDPS or GGPS1 elicited YAP nuclear exclusion. Furthermore, HMGCS silencing decreased expression of CTGF and CYR61, two known YAP targets. Finally, supplementation with geranylgeranyl pyrophosphate reverted YAP translocation and prevented actin and αSMA fiber reduction in the presence of statins. Simvastatin treatment lowered the expression of profibrotic genes CTGF, CYR61, ACTA2 and COL1A1 in HLF treated with TGF-β. Simvastatin also reduced fibrogenesis in vivo. In a therapeutic regime, mice were injected with bleomycin and treated with simvastatin after 14 days, at the peak of fibrosis. After two weeks of daily simvastatin administration, lung collagen content was significantly reduced in the treatment group. In addition, we observed a decrease in the percentage of nuclear YAP+ cells within the fibroblast population in the lungs of mice treated with simvastatin, showing target engagement in vivo. We have developed an effective screening platform for YAP inhibitors in HLF and validated statins as antifibrotic agents.