Tuberculosis and parasitic infections continue to impose a significant threat to global public health and economic growth. There is an urgent need to develop new treatments to combat these diseases. Here, we report the <i>in vitro</i> and <i>in vivo</i> profiles of a new bicyclic nitroimidazole subclass, namely, nitroimidazopyrazinones, against mycobacteria and <i>Trypanosoma cruzi</i>. Derivatives with monocyclic side chains were selective against <i>Mycobacterium tuberculosis</i> and were able to reduce the bacterial load when dosed orally in mice. We demonstrated that deazaflavin-dependent nitroreductase (Ddn) could act effectively on nitroimidazopyrazinones, indicating the potential of Ddn as an activating enzyme for these new compounds in <i>M. tuberculosis</i>. Oral administration of compounds with extended biaryl side chains (<b>73</b> and <b>74</b>) was effective in suppressing infection in an acute <i>T. cruzi</i>-infected murine model. These findings demonstrate that active nitroimidazopyrazinones have potential to be developed as orally available clinical candidates against both tuberculosis and Chagas disease.