Integrin β4 is a tissue-specific protein, but its role in autophagy of lung adenocarcinoma cells is not clear. In this study, we used microtubule-associated protein 1 light chain 3 processing and acridine orange staining to reveal that knockdown of integrin β4 by its specific siRNA induced autophagic cell death in A549 lung cancer cells. Next, we investigated the effects of siRNA-mediated downregulation of integrin β4 on cell death and the level of p53. The proportion of dead cells and level of p53 were significantly increased. Inhibition of autophagy by the inhibitor 3-methyladenine attenuated the cell death induced by integrin β4 knockdown. To further understand the relationship between p53 and integrin β4 in autophagic cell death, we inhibited the expression of integrin β4 by its specific siRNA in p53-mutated H322 lung cancer cells. Knockdown of integrin β4 could not induce autophagic cell death in H322 cells. The data suggest that integrin β4 is implicated in and associated with p53 in autophagy of lung cancer cells.