Background: Novel multitargeted antiangiogenic tyrosine kinase inhibitors (MATKIs) have showed promising advantages in combination with chemotherapy or as monotherapy in treatments of advanced non-small cell lung cancer (NSCLC). Since the efficacy and safety of these small molecules have been evaluated by several phase II/III randomized controlled trials (RCTs), we seek to summarize the current evidences by performing a meta-analysis. Methods: PubMed, EMBASE, the Cochrane Library as well as the ASCO and ESMO databases were searched for eligible literatures. We defined the experimental arm as MATKI-containing group while the control arm as MATKI-free group. The endpoints being evaluated included overall survival (OS), progression free survival (PFS), objective response rate (ORR) and disease control rate (DCR), as well as adverse events (AEs). Pooled hazard ratios (HRs) for survival outcomes and odds ratio (ORs) for dichotomous data, with 95% confidence intervals (CI) were calculated using REVMAN 5.0. Subgroup analysis was conducted according to each agent respectively. Results: Five agents (vandetanib, sunitinib, cediranib, sorafenib, motesanib) with comparable data could be analyzed. Fifteen phase II/III RCTs that involved a total of 8854 participants were included. Compared to MATKI-free group, MATKI-containing group was associated with significant longer PFS (HR 0.824, 95% CI 0.759 to 0.895, P<0.001), superior ORR (OR 1.27, 95% CI 1.13 to 1.42, P<0.0001) and DCR (OR 1.14, 95% CI 1.04 to 1.25, P=0.006). However, although some improvement in OS was observed, the benefit did not reach statistical significance (HR 0.962, 95% CI 0.912 to 1.015, P=0.157). In terms of subgroup results, sorafinib was revealed to yield no improvement in all endpoints. The specific AEs in patients who received these agents were rash, diarrhea and hypertension. Conclusions: Regimens consisting of multitargeted antiangiogenic TKIs were superior to those without these agents in terms of tumor response and PFS in patients with advanced NSCLC. However, no significant benefits in OS were observed. In addition, sorafinib seemed to has no substantial efficacy for NSCLC patients.