Lung fibrosis, characterized by persistent deposition of extracellular matrix to alveolar areas, is a progressive fibrotic disease, which leads to lung function decline and mortality. At the cellular level, myofibroblast activation and proliferation are the central cellular events of lung fibrosis. Here, through a functional genetics screen, we identify cyclin-dependent kinase 13 (CDK13) as a regulator of pro-fibrotic gene expression. Further analyses show that CDK13 cooperates with CDK12 and CDK7 to synergistically induce myofibroblast activation, contractility, and proliferation. Pharmacological inhibition of CDK7/12/13 by a small molecule inhibitor, THZ1, induces myofibroblast reprogramming and reverses myofibroblast activation . Consistent with these findings, we show that THZ1 ameliorates lung fibrosis and blocks myofibroblast activation and proliferation in the bleomycin model. These results reveal CDK7/12/13 as the previously unrecognized determinants of myofibroblast activation and lung fibrosis and support their functional synergism as a tractable therapeutic target for patients with fibrotic lung diseases.