Short-chain fatty acids are the major by-products of bacterial fermentation of undigested fibers in the colon. SCFAs, mostly propionate and butyrate, induce differentiation, growth arrest, and apoptosis in colon cancer cells. The anticancer effect of SCFAs is also supported by epidemiological studies suggesting an inverse relationship between the level of dietary fibers and the incidence of human colon cancer. Dietary components influence the risk of human colon cancer including colon cancer through diverse mechanisms, which include the activation or inhibition of autophagy (type II programmed cell death (PCD)). Herein we demonstrate that propionate and butyrate induce autophagy in human colon cancer cells to dampen apoptosis, whereas inhibition of autophagy potentiates SCFA-induced apoptosis. The propionate-induced autophagy originates from mitochondria defects associated with cellular ATP depletion and ROS generation, both of which contribute to AMPK activation and consequential mTOR inhibition. Remarkably, when autophagy is suppressed through either pharmacological or genetic approaches, the colon cancer cells become sensitized toward propionate-induced apoptotic cell death (type I PCD). Our study is the first report characterizing this novel role of SCFAs in orchestrating two types of programmed cell death. The observed pro-survival effects of autophagy in retarding mitochondria-mediated apoptosis suggest that application of an autophagy inhibitor might improve the therapeutic efficacy of SCFAs in inducing colon cancer suppression.