Circulating cell-free DNA (cfDNA), which can be obtained from plasma or serum by non-invasive procedures, has showed great potential to predict treatment response and survival for cancer patients. Several studies have assessed the prognostic and predictive value of cfDNA in non-small cell lung cancer (NSCLC). However, these studies were often small and reported varying results. To address this issue, a meta-analysis was carried out. A total of 22 studies involving 2518 patients were subjected to the final analysis. Our results indicated that NSCLC patients with higher cfDNA concentration had shorter median progression-free survival (PFS) and overall survival (OS) time. In addition, high levels of cfDNA were significantly associated with poor PFS (hazard ratio or HR, 1.32; 95% CI, 1.02-1.71) and OS (HR, 1.64; 95% CI, 1.26-2.15). With respect to tumor specific mutations, we failed to reveal significant differences for PFS (HR, 1.30; 95% CI, 0.66-2.56) and OS (HR, 1.05; 95% CI, 0.49-2.25) when NSCLC patients were grouped according to KRAS genotype detected in cfDNA. However, NSCLC patients which harbored EGFR activating mutation in cfDNA had a greater chance of response to EGFR-TKIs (odds ratio or OR, 1.96; 95% CI, 1.59-2.42). No significant publication bias was detected in this study. In conclusion, cfDNA could act as a prognostic and predictive biomarker for patients with NSCLC.