For many years, the role of interferon (IFN)-I has been characterized primarily in the context of viral infections. However, regulatory functions mediated by IFN-I have also been described against bacterial infections and in tumor immunology. Only recently, the interest in understanding the immune functions mediated by IFN-I has dramatically increased in the field of protozoan infections. In this review, we discuss the discrete role of IFN-I in the immune response against major protozoan infections: Plasmodium, Leishmania, Trypanosoma, and Toxoplasma.