Bacteria infect the endometrium lining the uterus of cattle after parturition, and clearance of these microbes depends on robust host tissue defenses. Animals under metabolic stress are at increased risk of postpartum uterine disease, which often leads to infertility. One hypothesis is that metabolic stress impairs host tissue defenses. Innate immunity is a key component of endometrial defense against bacteria. Innate immunity is predicated on host cell receptors that recognize pathogen-associated molecular patterns, and activated cells release inflammatory mediators. Cellular metabolism and innate immunity are highly integrated systems in tissues, and stressing one system might affect the other. Indeed, endometrial responses to the pathogen-associated molecular pattern, lipopolysaccharide, increases endometrial glucose consumption and induces aerobic glycolysis. Conversely, depriving endometrial tissues of their main energy substrates, glucose or glutamine, impairs their innate immune response to pathogen-associated molecular patterns. Furthermore, endometrial inflammatory responses to lipopolysaccharide are reduced by small molecules that modulate the intracellular sensor of energy, AMP-activated protein kinase. Metabolic stress also impacts lipid metabolism in cattle, and manipulating the mevalonate pathway, which precedes cholesterol synthesis, modulates inflammatory responses to pathogen-associated molecular patterns. However, other potential regulators of endometrial function, including mammalian target of rapamycin, insulin-like growth factor-1, and ovarian steroid hormones have limited impact on immunity. In conclusion, metabolic stress perturbs inflammatory responses to pathogen-associated molecular patterns in endometrial tissue, and fundamental regulators of cellular metabolism have the greatest impact on innate immunity.