Objective: To evaluate the efficacy and safety of multi-targeted tyrosine kinase inhibitor combined with erlotinib for advanced non-small lung cancer cell (NSCLC). Methods: The PubMed, Cochrane library, Web of Science, EMBASE, Wanfang database, CNKI and VIP were searched to identify randomized controlled trials about multi-targeted tyrosine kinase inhibitor combined with erlotinib for advanced NSCLC. The RCTs that conformed to the inclusion criteria were performed Meta-analysis via RevMan5.3 software. Results: Five trials with a total of 1 523 patients were included in this study. Meta-analysis suggested that the combination of erlotinib and multi-targeted tyrosine kinase inhibitor did not improve overall survival (OS) (HR=0.86, 95% CI: 0.69–1.07, P>0.05), but improved progression-free survival (PFS) (HR=0.68, 95% CI: 0.52–0.90, P<0.05), and objective response rate (ORR) (RR=1.46, 95% CI: 1.02–2.08, P<0.05). The incidences of grade 3/4 adverse events such as diarrhea, rash, asthenia/fatigue, anorexia, nausea/vomiting and thrombocytopenia (P<0.05) were higher in the combination group than those in the monotherapy group. For anemia, thromboembolic event, dehydration, hypertension and mucosal inflammation (P>0.05), overall analysis did not demonstrate a difference. Conclusion: The combination of multi-targeted tyrosine kinase inhibitor plus erlotinib is superior to erlotinib alone in terms of PFS and ORR in treatment of advanced NSCLC with an acceptable and manageable risk of toxicity. However, more large-scale trials are needed to prove these findings.