Both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are widely applied for the treatment of non-small cell lung cancer (NSCLC), but the efficacy of these two treatments in combination is not yet clear. Thus, we sought to evaluate the efficacy of the intercalated combination of these two treatments in NSCLC. The PubMed database, EMBASE, Cochrane Controlled Trials Register, and Chinese Biomedical Database were systematically searched by two researchers for randomized clinical trials (RCTs) that examined the intercalated combination of chemotherapy and EGFR TKIs in NSCLC. Ten studies involving 1,660 patients were included in this systematic review. The statistical results showed that the intercalated combination of chemotherapy and EGFR TKIs significantly improved overall survival (OS) (hazard ratio (HR) = 0.83, 95% confidence interval (CI): 0.70-0.98), progression-free survival (PFS) (HR = 0.65, 95% CI: 0.51-0.84), and the objective response rate (ORR) (risk ratio (RR) = 1.90, 95% CI: 1.22-2.98) compared to chemotherapy alone. Similarly, compared to EGFR TKIs monotherapy, the intercalated combination of chemotherapy and EGFR TKIs seemed superior to EGFR TKIs alone in terms of PFS, ORR and DCR (PFS: HR = 0.75, 95% CI: 0.62-0.91, ORR: RR = 1.49, 95% CI: 1.12-2.00 and DCR: RR = 1.33, 95% CI: 1.15-1.54) in advanced NSCLC therapy.