Abstract Background Isocitrate dehydrogenase (IDH) is an appealing target for anticancer therapy, and IDH (IDH1/2) inhibitors have been approved for targeted therapy of acute myeloid leukemia (AML) and Cholangiocarcinoma. The therapeutic potential of IDH inhibitors for non‐small‐cell lung cancer (NSCLC) patients is under active clinical investigation. Thus, it would be necessary and meaningful to study the molecular and clinical characteristics of IDH mutation in NSCLC patients, especially in the Chinese population. Methods A total of 17,978 Chinese patients with NSCLC who underwent next ‐generation sequencing (NGS) testing were retrospectively reviewed. Results We identified 161 unique IDH mutations in 361 of 17,978 patients (2.01%). Common active‐site mutations, including IDH1R100, IDH1R132, IDH2R140, and IDH2R172, were detected in 154 patients (0.86%) and were associated with male sex (p = 0.004) and older age (p = 0.02). The IDH mutation spectra observed in NSCLC were quite different from those in glioma or AML. Patients with IDH active‐site mutations exhibited significantly higher coalterations in KRAS (p. G12/13/61, 22.1% vs. 8.2%, p