We conducted a systematic review and meta-analysis to dissect the association between PIK3CA mutations and resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) according to PIK3CA exon of mutations in metastatic colorectal cancer (mCRC). We systematically identified studies exploring the association between PIK3CA mutations and clinical outcomes of mCRC patients treated with anti-EGFR MoAbs. The primary clinical outcomes included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The pooled relative risk (RR) or hazard ratio (HR) was estimated by using fixed effect model or random effect model according to heterogeneity between studies. Thirteen studies were considered eligible, with 576 mCRC patients included. In KRAS wild-type mCRC patients, we observed a lower ORR in patients with PIK3CA exon 20 mutations 3 studies, 377 patients; ORR = 0% versus 37%; RR = 0.25; 95% confidence interval (CI) 0.05–1.19; P = 0.082, although the result was not statistically significant because of the small sample size. Only one study provided survival data according to the PIK3CA exon of the mutations, in which PIK3CA exon 20 mutations were statistically significantly associated with shorter PFS (HR = 2.52; 95% CI 1.33–4.78; P = 0.013) and OS (HR = 3.29; 95% CI 1.60–6.74; P = 0.006) in KRAS wild-type mCRC patients treated with anti-EGFR MoAbs. The predictive power of exon 20 mutation is greater than exon 9 mutations and all exons mutations in terms of ORR, PFS, and OS. These analyses suggest that PIK3CA exon 20 mutations may be a potential biomarker for resistance to anti-EGFR MoAbs in KRAS wild-type mCRC.