The complexity and diversity of snake venoms cause a wide range of clinical manifestations in snakebites through the modulation and alteration of different systems, such as the innate immune response. Macrophages are involved in the development of the inflammatory response and in the hemostatic response through the expression and release of molecules involved in fibrin deposition and fibrinolysis. Based on their relevant role in the innate immune response, we employed monocyte-derived macrophages (MDM), after differentiation of the U937 cell line, as an in vitro model of the possible activation of the innate immunity by venoms and toxins from the venom of viperid and elapid snakes including Crotalus atrox, C. adamanteus, Agkistrodon p. piscivorus, Micrurus t. tener, Ophiophagus hannah, and KCV F2 (fraction from O. hannah venom). We performed cell activation assays after treatment for 1, 3, and 24 h with non-toxic concentrations of venom and toxins and measured critical molecules of the inflammatory response (TNF-α, IL-6, IL-8, and IL-10) and the hemostatic system (tissue factor and plasminogen activators -tPA and uPA-) in cells and supernatants of MDM. The samples modulated the macrophagic response differently. KCV F2 increased the release of the majority of the cytokines analyzed, while a lower release of IL-8 and IL-10 was seen after incubation for 24 h with M. t. tener, C. atrox, and C. adamanteus venoms, compared to untreated cells. Regarding the hemostatic activity, a remarkable release of tPA was seen after 24 h of incubation with whole venoms of C. atrox, C. adamanteus, and O. hannah, independent of the fibrinolytic activity of the venoms. These findings suggest a possible role of macrophages in the pathophysiology caused by the snake venoms studied. Further studies are necessary to elucidate the molecular pathways and toxins involved in the effects described.