The epidermal growth factor receptor (EGFR) signaling plays a key role in the initiation, progression, growth and metastases of colorectal carcinoma (CRC). Monoclonal antibody against EGFR (aEGFR; Cetuximab) has been used in treating CRC but some CRCs appeared to be resistant to aEGFR therapy, with undetermined mechanisms. Here, we studied the effects of aEGFR on CRC cells in vitro. We found that aEGFR dose-dependently activated Beclin-1 in 2 CRC cell lines, HT29 and SW480. Inhibition of autophagy significantly increased the aEGFR-induced CRC cell death in an CCK-8 assay. Moreover, microRNA (miR)-216b levels were significantly downregulated in aEGFR-treated CRC cells. Bioinformatics study showed that miR-216b targeted the 3'-UTR of Beclin-1 mRNA to inhibit its translation, which was confirmed by luciferase reporter assay. Together, these data suggest that aEGFR may decrease miR-216b levels in CRC cells, which subsequently upregulates Beclin-1 to increase CRC cell autophagy to antagonize aEGFR-induced cell death. Strategies that increase miR-216b levels or inhibit cell autophagy may improve the outcome of aEGFR treatment in CRC therapy.