Marfan syndrome (MFS) is a rare connective tissue disorder caused by mutations in FBN1. Patients with MFS notably suffer from aortic aneurysm and dissection. Despite considerable effort, animal models have proven to be poorly predictive for therapeutic intervention in human aortic disease. Patient-derived induced pluripotent stem cells can be differentiated into vascular smooth muscle cells (VSMCs) and recapitulate major features of MFS. We have screened 1,022 small molecules in our in vitro model, exploiting the highly proteolytic nature of MFS VSMCs, and identified 36 effective compounds. Further analysis identified GSK3β as a recurring target in the compound screen. GSK3β inhibition/knockdown did not ameliorate the proliferation defect in MFS-VSMCs but improved MFS-VSMC proteolysis and apoptosis and partially rescued fibrillin-1 deposition. To conclude, we have identified GSK3β as a novel target for MFS, forming the foundation for future work in MFS and other aortic diseases. Display omitted •Developed an iPSC-based drug screen for MFS and tested 1,022 small molecules•Identified GSK3β as a recurring target among effective small molecules•Validated the outcome of the drug screen using six GSK3β inhibitors and siRNA•GSK3β inhibition/knockdown decreased proteolysis and apoptosis in 4 patient lines Animal models of MFS have not yet been successful in predicting human disease. Sinha and colleagues have developed an iPSC model of MFS and used it as a platform for drug screening. They screened over a thousand compounds and identified GSK3β as a top drug target. This work is the foundation for further screening in MFS and related diseases.