Introduction: Toxoplasma gondii is a common zoonotic parasite that can cause serious congenital complications, such as neurological and ophthalmological disorders. While the placenta protects the fetus from pathogens, the immune response mechanisms to T. gondii are not well understood. This study focuses on how the infection affects the secretion of the host damage-associated molecular pattern S100A11, the activation of receptors RAGE and TLR4, and their role in maintaining placental barrier integrity and cytokine response against infection. Methods: Human placental explants (HPEs) were challenged with T. gondii tachyzoites or LPS as a positive control in the presence and absence of specific inhibitors for RAGE (FPS-ZM1) and TLR4 (TAK-242). Expression of both PRRs was assayed by Western blot, RT-qPCR, and immunohistochemistry; placental damage was studied by standard histopathological methods (Hematoxylin-Eosin and Masson's Trichrome stain), expression of intercellular adhesion proteins Occludin and E-cadherin was analyzed by immunohistochemistry, the secreted DAMPs profiles by ELISA and cytokines by multiplex bead array. Results: T. gondii infection induces the secretion and expression of S100A11 and its receptor RAGE. Inhibition of RAGE does not reduce T. gondii infection. Interestingly, simultaneous inhibition of RAGE and TLR4 decreases the parasite-induced histopathological damage of the placental barrier, intercellular proteins E-cadherin and Occludin expression, and parasite load. In addition, the secretion of IL-8, and TNF were modulated by RAGE and TLR4 inhibition. Conclusion: These results suggest that S100A11-RAGE/TLR4 axis activation is a significant mediator of the local placental immune response against T. gondii.