ABSTRACT Shigella flexneri is a major cause of bacillary dysentery in the developing world, predominantly affecting the pediatric age group, with malnutrition being a common co-morbidity. Lipids are key nutritional components, and their abundance and composition are likely to influence the pathobiology of S. flexneri. S. flexneri expresses a plethora of polysaccharides on its cell surface, but how this hydrophilic surface layer influences S. flexneri interaction with hydrophobic host molecules, such as fatty acids and lipids, is not well understood. In this study, we sought to interrogate how this hydrophilic layer affects S. flexneri during its intracellular lifestyle and how lipid homeostasis changes in both the host and pathogen. We characterized changes in S. flexneri cell envelope composition and surface-associated glycolipids, in particular lipopolysaccharide (LPS), during different phases of infection. We found that a dynamic capacity in LPS expression is necessary for the pathogen to manage delicate interaction with host fatty acids and maintain optimum virulence. Additionally, through confocal immunofluorescent microscopy, coupled with transcriptional and lipid analyses, we demonstrate that S. flexneri induces major host lipid remodeling during infection, by hijacking host lipid homeostasis pathways to its own benefit. Finally, this study suggests that fatty acid supplementation can influence the persistence and magnitude of S. flexneri infection. This work provides novel insights into the potential roles of balanced and sufficient dietary fatty acid intake in protection against gastroenteric pathogen infection. IMPORTANCE Bacterial pathogens have vastly distinct sites that they inhabit during infection. This requires adaptation due to changes in nutrient availability and antimicrobial stress. The bacterial surface is a primary barrier, and here, we show that the bacterial pathogen Shigella flexneri increases its surface decorations when it transitions to an intracellular lifestyle. We also observed changes in bacterial and host cell fatty acid homeostasis. Specifically, intracellular S. flexneri increased the expression of their fatty acid degradation pathway, while the host cell lipid pool was significantly depleted. Importantly, bacterial proliferation could be inhibited by fatty acid supplementation of host cells, thereby providing novel insights into the possible link between human malnutrition and susceptibility to S. flexneri .