Aim This study aimed to compare anti-epidermal growth factor receptor (anti-EGFR) therapy and anti-vascular endothelial growth factor therapy as first-line and second-line therapies in patients with KRAS exon 2 codon 12/13 wild-type (KRAS-WT) metastatic colorectal cancer (mCRC). Methods Major databases were systematically searched. The hazard ratio (HR), odds ratio (OR), and 95% confidence intervals (95% CIs) were used to estimate the effect measures. Review Manager software version 5.3 was used for statistical analysis. Results Seven trials including ten articles were eligible in the meta-analysis. The patients treated with anti-EGFR as first-line therapy showed a longer overall survival (OS) for KRAS-WT and all RAS wild-type (RAS-WT) mCRC (HR =0.81, 95% CI: 0.72–0.92, P<0.01, n=5; HR =0.78, 95% CI: 0.66–0.93, P<0.01, n=3, respectively). The objective response rate (ORR) was better with the anti-EGFR therapy for KRAS-WT and all RAS-WT mCRC (OR =1.32, 95% CI: 1.11–1.56, P<0.01, n=5; OR =1.55, 95% CI: 1.21–2.00, P<0.01, n=3, respectively). There was no difference in progression-free survival (PFS) for KRAS-WT mCRC and all RAS-WT mCRC between the two groups (HR =1.00; 95% CI: 0.92–1.09, P=0.99, n=4; HR =0.92, 95% CI: 0.71–1.19, P=0.52, n=3, respectively). In addition, two trials provided data on the second-line therapy; there was no significant difference in OS and PFS for the second-line therapy, but a significant improvement in ORR was found in the anti-EGFR group (OR =1.91, 95% CI: 1.16–3.16, P=0.01, n=2). No difference in the conversion therapy (OR =1.34; 95% CI: 0.91–1.99; P=0.14, n=4) was observed between the two therapies. Conclusion Our results indicate that anti-EGFR therapy is superior to anti-vascular endothelial growth factor therapy for OS and ORR as a first-line therapy for KRAS-WT mCRC. In the second-line therapy, there was no significant difference in the survival outcomes on the basis of OS and PFS between the two groups. However, ORR improved significantly in the anti-EGFR group.