Short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate are metabolic products of anaerobic bacteria fermentation in the intestine. These fatty acids play a crucial role in modulating various processes in the gastrointestinal (GI) tract, including electrolyte and water absorption. They have also been recognized as potential mediators involved in the effects of gut microbiota on intestinal immune function. SCFAs act on leukocytes and endothelial cells through at least two mechanisms: activation of G protein-coupled receptors (GPCRs) (GPR41 and GPR43) and inhibition of histone deacetylase (HDAC). SCFAs regulate several leukocyte functions, including the production of cytokines (TNF-α, IL-2, IL-6, and IL-10), eicosanoids, and chemokines (e.g., MCP-1 and CINC-2). They also affect the migration of leukocytes to inflammatory sites and their ability to destroy microbial pathogens. This review discusses the latest research on how SCFAs regulate the inflammatory process, focusing on their effects on isolated cells (leukocytes, endothelial, and intestinal epithelial cells) and the recruitment and activation of leukocytes. The therapeutic application of these fatty acids for treating inflammatory pathologies is also highlighted.Short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate are metabolic products of anaerobic bacteria fermentation in the intestine. These fatty acids play a crucial role in modulating various processes in the gastrointestinal (GI) tract, including electrolyte and water absorption. They have also been recognized as potential mediators involved in the effects of gut microbiota on intestinal immune function. SCFAs act on leukocytes and endothelial cells through at least two mechanisms: activation of G protein-coupled receptors (GPCRs) (GPR41 and GPR43) and inhibition of histone deacetylase (HDAC). SCFAs regulate several leukocyte functions, including the production of cytokines (TNF-α, IL-2, IL-6, and IL-10), eicosanoids, and chemokines (e.g., MCP-1 and CINC-2). They also affect the migration of leukocytes to inflammatory sites and their ability to destroy microbial pathogens. This review discusses the latest research on how SCFAs regulate the inflammatory process, focusing on their effects on isolated cells (leukocytes, endothelial, and intestinal epithelial cells) and the recruitment and activation of leukocytes. The therapeutic application of these fatty acids for treating inflammatory pathologies is also highlighted.