The innate immune response is highly dependent on the action of macrophages. They are abundant in the intestine subepithelial lamina propria of the mucosa, where they deploy multiple tasks and play a critical role. The balance between the gut microbiota and M2 macrophages is critical for gut health and homeostasis. Gut microbiota has the power to change macrophage phenotype and replenish the resident macrophage niche during and post infection. As far as the extracellular enteric parasitic infections invasive amebic colitis and giardiasis are concerned, a change of macrophages phenotype to a pro-inflammatory state is dependent on direct contact of the protozoan parasites with host cells. Macrophages induce strong pro-inflammatory response by inflammasome activation and secretion of interleukin IL-1β. Inflammasomes play a key role in the response to cellular stress and microbe attacks. The balance between gut mucosal homeostasis and infection is dependent on the crosstalk between microbiota and resident macrophages. Parasitic infections involve NLRP1 and NLRP3 inflammasome activation. ForEntamoeba histolyticaandGiardia duodenalisinfections, inflammasome NLRP3 activation is crucial to promote the host defenses. More studies are needed to further elucidate possible therapeutic and protective strategies against these protozoan enteric parasites’ invasive infections in humans.