Purpose: The epidermal growth factor receptor (EGFR) is one of the four human epidermal receptors. The efficacy and safety of EGFR-targeted therapies for treating non-small-cell lung cancer (NSCLC) remained controversial. The aim of this study was to systematically evaluate EGFR-targeted therapies plus chemotherapy for advanced NSCLC. Methods: Cochrane Central Register of Controlled Trials, PubMed, and Embase were searched for relevant studies. Quantitative analysis was carried out to evaluate survival, response, and toxicity of EGFR-targeted therapies. Results: Ten randomized controlled trials (RCTs) involving 5,936 patients were identified out of 107 studies. There was no statistical difference in overall (OS) and 1-year (OYS) survival rate when small-molecule tyrosine kinase inhibitors (TKIs) plus platinum-based doublet chemotherapy (PBDC) were compared with PBDC alone. However, progression-free survival [hazard ratio (HR) = 0.87, 95% confidence interval (CI) 0.76-0.99] and overall response rate (ORR) were marginally improved. Prolonged OS (HR = 0.87, 95% CI 0.78-0.96) and increased ORR and OYS were found when cetuximab plus PBDC was compared with PBDC alone. Adverse events in the combination arms were similar in incidence to those of the chemotherapy-alone arms, with the exception of an increased incidence of rash and diarrhea. Conclusions: Cetuximab adds benefits to NSCLC patients compared with PBDC alone. Small-molecule TKIs plus PBDC lead to a slightly additive efficacy compared with PBDC alone.