The prognosis of pancreatic cancer remains dismal despite continuous and considerable efforts. Integrins (ITGs) are highly expressed in various malignant cancers. However, very few studies investigated the role of integrin alpha 3 (ITG alpha 3) in malignant cancers. Here, we determined the functional role of ITG alpha 3 in pancreatic cancer. Analysis of public microarray databases and Western blot analysis indicated a unique expression of ITG alpha 3 in human pancreatic cancer. Silencing ITG alpha 3 expression significantly inhibited the viability and migration of human pancreatic cancer cells. Notably, ablation of ITG alpha 3 expression resulted in a significant decrease of epidermal growth factor receptor (EGFR) expression compared with transfection of control-siRNA through an increased number of leucine-rich repeats and immunoglobulin-like domain protein 1 (LRIG1) expression. In addition, ablating ITG alpha 3 inhibited tumour growth via blockade of EGFR signalling in vivo. Furthermore, the highly expressed ITG alpha 3 led to a poor prognosis of pancreatic cancer patients. Our results provide novel insights into ITG alpha 3-induced aggressive pancreatic cancer.