High-fat diets (HFDs) are major environmental factors influencing metabolic homeostasis, immune regulation, and brain function, largely through their effects on gut microbiota and intestinal barrier integrity. Disruption of the microbiome–brain–gut axis has been increasingly implicated in systemic and neuroinflammatory processes; however, the molecular mediators that integrate dietary lipid signals with microbial and host responses remain incompletely defined. This review synthesizes the current evidence on the role of fatty acid-binding protein 4 (FABP4) as an integrative node linking HFD-induced gut dysbiosis to systemic and central inflammatory signaling. We critically evaluated experimental and translational studies addressing HFD-driven alterations in gut microbiota composition, intestinal barrier function, and inflammatory pathways, with particular emphasis on FABP4-mediated mechanisms across epithelial, immune, and neural compartments. The available data indicate that FABP4 responds to dietary and microbiome-derived cues and contributes to coordinated metabolic and inflammatory responses, affecting both peripheral tissues and the central nervous system. These findings support a model in which FABP4 participates in diet-driven feedback loops that amplify gut barrier dysfunction, immune activation, and neuroinflammation. In conclusion, FABP4 emerges as a central molecular mediator within the microbiome–brain–gut axis under HFD conditions, highlighting its potential relevance in understanding the pathophysiology of metabolic and neuroinflammatory disorders and guiding future integrative research strategies.