Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive lethal diseases among other cancer types. Gut microbiome and its metabolic regulation play a crucial role in PDAC. Metabolic regulation in the gut is a complex process that involves microbiome and microbiome-derived short-chain fatty acids (SCFAs). SCFAs regulate inflammation, as well as lipid and glucose metabolism, through different pathways. This review aims to summarize recent developments in PDAC in the context of gut and oral microbiota and their associations with short-chain fatty acid (SCFA). In addition to this, we discuss possible therapeutic applications using microbiota in PDAC.