Objective: To explore the value of clinicopathological features combined with serum carcinoembryonic antigen (CEA) in predicting epidermal growth factor receptor (EGFR) mutation in patients with non-small cell lung cancer (NSCLC), and the relationship with therapeutic effect. Methods: A total of 180 patients with NSCLC who were admitted to the hospital from July 2015 to January 2021 were selected as the research subjects, and their clinicopathological data was collected. Meanwhile, serum CEA and EGFR mutation were determined. The value of clinicopathological features and serum CEA in predicting EGFR mutation, as well as the influencing factors of therapeutic effect was analyzed. Results: The EGFR mutation rate in the 180 patients with NSCLC was 40.00% (72/180). Univariate analysis and multivariate logistic regression analysis showed that histological type, lymph node metastasis, and serum CEA were factors influencing EGFR mutation (P<0.05), whereas gender and smoking history were not factors influencing EGFR mutation (P>0.05). Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) values of histological type, lymph node metastasis, and CEA for predicting EGFR mutation were 0.869, 0.627 and 0.768, and the AUC of combined prediction with the three was 0.953. Univariate analysis and multivariate logistic regression analysis showed that histological type, CEA, and EGFR mutation were factors influencing the therapeutic effect (P<0.05), whereas clinical staging and lymph node metastasis were not factors influencing the therapeutic effect (P>0.05). Conclusion: The incidence of EGFR mutation is relatively high in patients with NSCLC. Some clinicopathological features combined with serum CEA level is helpful for predicting EGFR mutation. Histological type, serum CEA, and EGFR mutation are closely related to the therapeutic effect, which provides reference for treatment.