The increasing dominance of multidrug resistance demands that we deepen our understanding of how bacterial superbugs and their hosts’ systems adapt to one another. From both perspectives, the battlefront of infection is a balancing act of nutrient processing, which includes lipid homeostasis. For bacteria, maintenance of the lipid pool facilitates energy supplementation and the membrane’s dynamic biophysical properties. This sustains the function of countless proteins essential for adaptation to changing environments. For their hosts, changes in lipid processing are important for immune function, mucosal surface integrity and infection control. While much of the biochemistry behind lipid processing in bacteria and humans have been described, the mechanisms regulating lipid homeostasis in response to dynamic infectious stresses have only recently begun to be appreciated. Following exposure to an immune-activated host niche, human ascites fluid, we observed a prominent fatty acid hypersaturation in Klebsiella pneumoniae and Acinetobacter baumannii. Further, artificially priming cultures with this phenotype improved their viability in this environment. The importance of lipid storage processing to the host’s control of infection was also observed in an infection model of mice given diets of differing lipid content. Bacterial infection yielded greater numbers and altered morphologies of mouse liver lipid droplets. This coincided with a shifted composition of lipid storage sites that was intensified in high fat diets. Significantly, an omega-3 fatty acid enriched diet reduced bacterial performance. Together, these findings demonstrate the importance of maintaining lipid homeostasis to the viability of both bacterium and host. A hitherto uncharacterised lipid stress response was seen across bacterial families in diverse clinically relevant environments and may offer invaluable insight into how they evade our immunity and medical interventions. Further, our work shows the potential for manipulating the host lipid landscape through dietary intake as a mechanism to tip the scales in our favour during infection.