Cutaneous leishmaniasis, caused by Leishmania braziliensis, still represents a serious health problem in Brazil, especially in the northeast region. Currently, to our knowledge, no report describes the role of hypoxia inducible factor-1α (HIF-1α) during L braziliensis infection. In this study, we demonstrated that the parasite induces HIF-1α expression and stabilization in bone marrow-derived macrophages only when added with exogenous IFN-γ plus lipopolysaccharide. Coherently, we did not find an enrichment in the glycolytic pathway upon bone marrow-derived macrophage infection. Evaluating the impact of HIF-1α absence during macrophage infection in vitro, we observed HIF-1α-knockout cells present at high levels of IL-10, reduced production of nitric oxide, and decreased expression of VEGF-A. As a result, parasite viability improves within HIF-1α-knockout cells. However, in vivo, the absence of myeloid cells expressing HIF-1α had no influence on nitric oxide at tissue levels and in parasite burden. Conversely, lack of HIF-1α significantly affects L braziliensis-induced pathology. Ear lesions induced in myeloid HIF-1α-knockout mice were thicker, presenting higher frequency of macrophages, neutrophils, CD4+, and CD8+ T cells as well as higher levels of IL-12, IL-1β, and IFN-γ, compared with those in wild-type mice. Moreover, draining lymph nodes from myeloid HIF-1α-knockout mice also harbored increased populations of T cells. Our data demonstrate that HIF-1α plays an important role during L braziliensis infection influencing skin pathology in vivo.