Neonates are particularly prone to digestive and respiratory infections due to the immaturity of their immune systems. TLR-ligands are powerful stimulants of the innate immune system. In this study, we investigated the role of TLR3 stimulation in neonate mice to control Cryptosporidium parvum development in epithelial cells of the intestine. Following poly(I:C) administration, a rapid reduction in parasite burden was observed which further required the presence of TRIF signaling molecules and CD11c+ cells. However, the protective effect of poly(I:C) was significantly reduced when the gut flora of neonates was diminished by an antibiotic treatment. Therefore in addition to TRIF signaling, the mechanism of protection depends on the presence of additional signals from the commensal flora. Using several different deficient mouse models, we demonstrated that the presence of MyD88 signaling is necessary but the mechanism of protection is independent of TLR2, TLR4 and TLR9. This synergy between TRIF and Myd88 signaling allowed for a higher level of expression of type I IFN and IL-12p40; two cytokines necessary to the poly(I:C) induced protection. The observed decrease in parasite burden was independent of the presence of functional T cells but poly(I:C) administration was associated with NKp46+ cell activation and an increase in their intracellular IFNγ. IFNγ has previously been shown to play a key role in the elimination of C. parvum infected enterocytes. Overall these data demonstrate that the commensal flora provides the additional signals to poly(I:C) stimulation to induce strong dendritic cell activation and subsequent control of parasite replication.