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Abstract Anlotinib is a multitargeted antiangiogenic drug, and its clinical predictor for responsive non‐small cell lung cancer (NSCLC) patients is still elusive. Here, tumor‐specific target capture is used to profile the circulating DNA of ALTER0303 (evaluating NSCLC clinical antitumor efficacy through anlotinib therapy) study participants. The results indicate that patients receiving no benefit can be mainly excluded via analysis of ARID1A and BRCA2 genetic profiling. For patients with no durable benefit and durable clinical benefit patients, three predictors: germline and somatic mutation burden (G+S MB), nonsynonymous and synonymous mutation burden (N+S MB), and unfavorable mutation score of circulating DNA profiling are identified. Through integrating the advantages and disadvantages of three independent predictors, the tumor mutation index (TMI) is established as a prediction model and the patients who are very likely to benefit more from anlotinib therapy are identified. Furthermore, the IDH1exon 4 mutation is identified as an unfavorable factor for anlotinib therapy under TMI‐based stratification, and the TMI plus IDH1exon 4 mutation status potentially predicts response to anlotinib. Collectively, this study provides a circulating DNA sequencing–based stratification method for identifying anlotinib responders via a noninvasive approach, and thus potentially improves the clinical outcome of NSCLC patients receiving third‐line therapy.