Leishmaniasis is a neglected tropical disease affecting millions of individuals worldwide. P2X7 receptor has been linked to the elimination of Leishmania amazonensis . Biological responses evoked by P2X7 receptor activation have been well-documented, including apoptosis, phagocytosis, cytokine release, such as IL-1β. It was demonstrated that NLRP3 inflammasome activation and IL-1β signaling participated in resistance against L . amazonensis . Furthermore, our group has shown that L . amazonensis elimination through P2X7 receptor activation depended on leukotriene B 4 (LTB 4 ) production and release. Therefore, we investigated whether L . amazonensis elimination by P2X7 receptor and LTB 4 involved NLRP3 inflammasome activation and IL-1β signaling. We showed that macrophages from NLRP3 -/- , ASC -/- , Casp-1/11 -/- , gp91 phox-/- , and IL-1R -/- mice treated with ATP or LTB 4 did not decrease parasitic load as was observed in WT mice. When ASC -/- macrophages were treated with exogenous IL-1β, parasite killing was noted, however, we did not see parasitic load reduction in IL-1R -/- macrophages. Similarly, macrophages from P2X7 receptor-deficient mice treated with IL-1β also showed decreased parasitic load. In addition, when we infected Casp-11 -/- macrophages, neither ATP nor LTB 4 were able to reduce parasitic load, and Casp-11 -/- mice were more susceptible to L . amazonensis infection than were WT mice. Furthermore, P2X7 -/- L . amazonensis- infected mice locally treated with exogenous LTB 4 showed resistance to infection, characterized by lower parasite load and smaller lesions compared to untreated P2X7 -/- mice. A similar observation was noted when infected P2X7 -/- mice were treated with IL-1β, i.e., lower parasite load and smaller lesions compared to P2X7 -/- mice. These data suggested that L . amazonensis elimination mediated by P2X7 receptor and LTB 4 was dependent on non-canonical NLRP3 inflammasome activation, ROS production, and IL-1β signaling.