Objective: To investigate the effect of apatinib combined with chemotherapy on multiple tumor markers in patients with advanced non-small cell lung cancer (NSCLC) and its short-term efficacy. Methods: A total of 68 patients with advanced NSCLC admitted to our hospital from March 2017 to June 2020 were selected, and all of them were confirmed by imaging and histopathology. They were randomly divided into a control group and a study group, with 34 cases in each group. The control group was treated with platinum containing double drug chemotherapy, while the study group was treated with apatinib on the basis of the control group. The levels of serum tumor markers (CEA, VEGF, CYFRA21-1) and the short-term efficacy of solid tumors were compared between the 2 groups. Results: The disease control rate (DCR) of the study group was 82.35%, which was higher than 58.82% of the control group. The median progression free survival (PFS) of the study group was 6.3 months, which was longer than 4.7 months of the control group, and the difference was statistically significant (P<0.05). The levels of CEA, VEGF and CYFRA21-1 in the two groups after the treatment were lower than those before the treatment, and the levels of VEGF and CYFRA21-1 in the study group after the treatment were lower than those in the control group, and the difference was statistically significant (P<0.05). The adverse reactions of the two groups were evaluated according to the toxicity evaluation standard (CTC), and the main adverse reactions were grade I–II, and there was no significant difference in the adverse reaction rate between the 2 groups (P>0.05). Conclusion: Apatinib combined with chemotherapy has a significant short-term effect in the treatment of NSCLC, can significantly reduce the serum VEGF and CYFRA21-1 levels, improve DCR and prolong PFS, with good safety.