Silicosis, the most common type of pneumoconiosis, exhibits a high incidence in workers who are chronically exposed to crystalline silica (CS). No specific remedy for cure as yet. The terpenoid oridonin exerts multiple modulatory functions in neoplasms and inflammations as a natural compound. In this study, we explored the effect of oridonin on silicosis and revealed the underlying molecular mechanism. An experimental silicosis mouse model was established to evaluate the effects of oridonin on pneumonia and pulmonary fibrosis. In addition, the impact of oridonin on alveolar macrophages (AMs) was examined in the MH-S cell line. Its molecular target, inducible nitric oxide synthase (iNOS), was identified by chemobiological means, and virus-mediated gene overexpression systems confirmed that oridonin directly restrained iNOS protein levels. Oridonin alleviated pneumonia and pulmonary fibrosis in silicosis mice with no obvious systemic toxicity. These effects were partially related to oridonin inhibition of CS-induced AMs injury and inflammation. Furthermore, oridonin suppressed iNOS enzymatic expression and activity by covalently binding to the Thr109 residue of the iNOS target. Thus, our results indicate oridonin as a potential iNOS enzymatic suppressor in experimental silicosis that attenuates pneumonia and pulmonary fibrosis progression, which provides a therapeutic avenue for silicosis prevention and treatment.