Introduction: To estimate the efficacy and safety of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) in combination with chemotherapy for patients with advanced non-small cell lung cancer (NSCLC). Methods: We searched PubMed, PMC database, EMBASE, EBSCO-Medline, Cochrane Central Register of Controlled Trials (CENTRAL), American Society of Clinical Oncology (ASCO), International Association for the Study of Lung Cancer (IASLC) and the European Society of Medical Oncology (ESMO), http://www.clinicaltrials.gov/, CNKI, and Wanfang databases to identify primary research reporting the survival outcomes and safety of VEGFR-TKIs in patients with advanced NSCLC. A meta-analysis was conducted to generate combined hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and risk ratios (RRs) with 95% CI for adverse events (AEs). Results: A total of 20 RCTs (8,366 participants) were included. The VEGFR-TKIs resulted in improved PFS (HR 0.82, 95% CI 0.78-0.87), ORR (HR 1.72, 95% CI 1.34-2.22), and DCR (1.45, 1.26-1.67) in patients with advanced NSCLC, but had no impact on OS (HR 0.94, 95% CI 0.89-1.00). The incidence of some high grade (>= 3) AEs increased, such as hemorrhage, hypertension and neutropenia. Conclusions: Our study demonstrated that regimens with VEGFR-TKIs combined with chemotherapy improved PFS, ORR and DCR in patients with advanced NSCLC, but had no impact on OS. VEGFR-TKIs induced more frequent and serious AEs compared with control therapies.