Poorly controlled glucose observed in obese individuals with diabetes is associated with a significantly increased risk of infection, particularly in the skin and soft tissues. Staphylococcus aureus is a significant cause of skin and soft tissue infections (SSTIs) in obese and hyperglycemic individuals with growing antibiotic resistance making these infections difficult to treat. However, the events that drive dysregulated skin host defense during hyperglycemia remain to be fully elucidated. Here we examined how the prostaglandin E2 (PGE2) threshold impacts tissue injury and host defense during methicillin-resistant S. aureus (MRSA) skin infection in obese and hyperglycemic mice. Our data show that obesity and hyperglycemia are accompanied by impaired expression of prostaglandin E synthase 1 and PGE2 production in infected skin. Restoration of PGE2 levels with the PGE analog misoprostol improved infection outcomes in obese and hyperglycemic mice in a manner dependent on E prostanoid 3-mediated cAMP inhibition. Topical misoprostol restored the levels of CXC chemokines and CXCR2+ monocyte and neutrophil recruitment. Here, we are unveiling a defective signaling program that culminates in inadequate CXCR2 phagocyte migration to the infected skin of obese and hyperglycemic mice. Furthermore, these data also lead to a novel drug repurposing opportunity to treat antibiotic-resistant pathogens in hyperglycemic conditions.