Autophagy is a process for delivering cytoplasmic material and organelles to lysosomes for degradation that protects cells during stress responses. Bax inhibitor-1 (BI-1) is an endoplasmic reticulum (ER) membrane protein that protects cells against ER stress and apoptosis. However, the function of BI-1 to modulate autophagy is still controversial. We showed BI-1 overexpression promotes autophagy, increasing LC3-II conversion and p62 degradation. BI-1-deficient mice and BI-1 knockout MEF cells have reduced autophagy. Moreover, BI-1 reduced mitochondria ATP levels, increasing AMPK activation, suppressing mTORC1 and stimulating autophagy. Thus, BI-1 promotes autophagy which contributes to cell survival, presumably in order to compensate for the impairment in mitochondria respiration.