The balance between the protozoans virulence and host immune responses (invertebrates and/or vertebrates) is crucial for the successful completion of the life cycle of these parasites in their hosts. Strategies such as macromolecules secretion, resistance to oxidative species, and silencing of macrophages, among many others, are applied by the parasites to evade host defenses. In this context, redox balance and biochemical mechanisms implicated by the parasitic protozoans represent a promising starting point for the development of novel anti-parasitic drugs and vaccines, and for testing their efficacy in preclinical and clinical trials. Reactive oxygen species (ROS) participate in regulating the protozoans’ infection asis extensively reported in the literature. Antioxidant enzymes expressed by the parasites play a biological role as virulence factors, contributing to the complexity of the parasite-host relationship. In this Research Topic, cellular, molecular, and biochemical aspects of the interactions of pathogenic protozoans and their hosts with a focus on parasite survival, dissemination, and evasion of host immune responses, and the suggestion of novel strategies for parasite elimination were addressed.