The complex interactions between Leishmania and macrophages are central to the outcome of parasite infection. Disrupting signaling molecules to impair macrophage function, is a subversive strategy used by several pathogens. In the present study, we show that the initial contact of Leishmania with human naïves macrophages and murine Raw264.7 macrophage cell line induced a rapid and transient activation of extracellular-signal-regulated kinases 1 and 2 (ERK1/2) and p38MAPK. This activation is an actin-dependent mechanism that requires internalization of live parasites. Once stably infected, macrophages become unresponsive to subsequent parasite infection. Priming of cells with IFNγ, prior to Leishmania infection, did not prevent the silencing of MAPKs pathways induced by Leishmania parasites. NF-κB transcriptional activity in response to Leishmania infection is also impaired in stably infected cells. This impairment was not due to MAPK deactivation as inhibition of ERK1/2 and p38MAPK, actually enhances the transcriptional activity of NF-κB in response to initial contact of Leishmania with the murine macrophagic cell line Raw264.7. Moreover, Leishmania parasites could not reverse the hyporesponsive state induced by LPS. These effects do not reflect a general down-regulation of macrophages signaling by parasites, as cells with established Leishmania infection display normal response to PMA. In addition we show that the mechanisms of Leishmania-induced hyporesponsive state is not due to the induction of a cellular tyrosine phosphatase activity as previously reported in LPS treated cells.