Purpose: To investigate the relationship between the changes of lactate dehydrogenase (LDH), neuron‐specific enolase (NSE), keratin‐19 fragment antigen 21‐1 (cyfra21‐1), and liver metastases of lung cancer.Methods: Eighty patients who had lung cancer that had spread to their liver diagnosed in our hospital from October 2021 to October 2023 (Group A), 80 individuals with advanced lung cancer who have metastasized to other sites (Group B), and 80 individuals with lung cancer who have not spread (control group) were selected as the study objects. LDH, NSE, and serum cyfra21‐1 levels of patients in the three groups were detected, and pathological results were used as the diagnostic gold standard. ROC curves were drawn to examine the clinical value of NSE, cyfra21‐1, and LDH levels in the distinct types of lung cancer identification of liver metastases.Results: There was no remarkable variation in pathological types among the three groups (p > 0.05), but there were remarkable variations in TNM stage and lymph node metastasis among the three groups (p < 0.05). The levels of cyfra21‐1, NSE, and LDH in Group A and Group B were greater compared to those in the control group (p < 0.05), and the levels of cyfra21‐1, NSE, and LDH in Group A were greater compared to those in Group B (p < 0.05). The critical value, sensitivity, specificity, and area under the curve (AUC) of serum cyfra21‐1 in the distinct identification of liver metastasis of lung cancer were 8.22 ng/mL, 37.42%, 65.18%, and 0.508, respectively. The critical value, sensitivity, specificity, and AUC of NSE for distinct types of lung cancer identification of liver metastases were 23.96 ng/mL, 64.56%, 81.23%, and 0.723, respectively. The critical value, sensitivity, specificity, and AUC of LDH for differential diagnosis of liver metastasis of lung cancer were 304.78 U/L, 75.65%, 85.73%, and 0.821.Conclusion: The serum levels of NSE, cyfra21‐1, and LDH in patients with liver metastasis of lung cancer were remarkably greater compared to patients without liver metastasis, which can be useful as a clinical auxiliary in determining lung cancer metastasis.