Bacterial infections remain an important clinical challenge despite our extensive arsenal of antibiotics. This is exemplified by lengthy treatments of chronic infections, high mortality due to excessive inflammation, and an alarming increase in antibiotic resistance. One attractive strategy for improved treatments for challenging infections is to enhance the host anti-microbial defence. We and others have associated the WNT signaling pathway with bacterial infections in patients and model systems, implicating novel immune-related functions for this well-known developmental signaling pathway. However, the nature of its contribution to the host response to infection remains to be clearly defined. In this study, we show differential expression of multiple WNT ligands in macrophages and intestinal epithelial cells infected with Listeria monocytogenes. Listeria burden was increased in WNT-overexpressing cells, whereas treatment with small molecule inhibitors of WNT production led to restriction of Listeria replication by infected host cells. This was associated with significant alterations in the Listeria-containing intracellular compartments, suggesting that WNT proteins guide the intracellular fate of ingested bacterial pathogens. Inhibition of WNT production in vivo significantly lowered bacterial burden of infected organs underpinning the relevance of our findings to the host control of Listeria infection. These observations affirm the functions of WNT proteins in the immune defence against infection and warrant the exploration of WNT pathway modulation to enhance endogenous host control mechanisms against pathogenic bacteria.