Short-chain fatty acids (SCFA) can regulate appetite by stimulating the secretion of satiety hormones. However, the impact of short-chain fatty acid propionate on the release of gut satiety hormones and appetite regulation in pigs is not completely understood. In this study, 16 pigs were infused with saline or sodium propionate through a fistula in the caecum during a 28-day experimental period. We characterized the effects of propionate administration on peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) secretion from colonic tissue, and investigated the role of propionate infusion on the expression of appetite-related genes in the colon and hypothalamus. Further, the direct impact of propionate administration on the expression of orexigenic neuropeptide agouti-related protein () in hypothalamic N38 cells was also examined. The results showed that intra-cecal infusion of propionate reduced the short-term feed intake ( < 0.05) but not the long-term feed intake in pigs ( > 0.05). Propionate administration stimulated PYY and GLP-1 release from colon tissue in vivo and ex vivo ( < 0.05). It also upregulated expression in the colonic mucosa ( < 0.05). Meanwhile, the GLP-1 and PYY levels in the blood were increased after intra-cecal infusion of propionate at d 28 ( < 0.05). Additionally, intra-cecal infusion of propionate upregulated the mRNA and protein expression of free fatty acid receptor 2/3 (FFAR2/FFAR3) in the colonic mucosa ( < 0.05). Propionate infusion also downregulated the orexigenic mRNA expression ( < 0.05) and upregulated the anorexigenic cocaine-and amphetamine-regulated transcript () mRNA expression ( = 0.09) in the hypothalamus. Moreover, propionate administration directly downregulated expression in hypothalamic N38 cells in a dose-dependent manner ( < 0.05). Collectively, these findings demonstrated that cecal propionate stimulated colonic secretion of satiety hormones and suppressed appetite to reduce the short-term feed intake in pigs. This study highlights that microbial-derived propionate exerts an important role in regulating the physical functions of the host.