Body tissues are subjected to various oxygenic gradients and fluctuations and hence can become transiently hypoxic. Hypoxia-inducible factor (HIF) is the master transcriptional regulator of the cellular hypoxic response and is capable of modulating cellular metabolism, immune responses, epithelial barrier integrity, and local microbiota. Recent reports have characterized the hypoxic response to various infections. However, little is known about the role of HIF activation in the context of protozoan parasitic infections. Growing evidence suggests that tissue and blood protozoa can activate HIF and subsequent HIF target genes in the host, helping or hindering their pathogenicity. In the gut, enteric protozoa are adapted to steep longitudinal and radial oxygen gradients to complete their life cycle, yet the role of HIF during these protozoan infections remains unclear. This review focuses on the hypoxic response to protozoa and its role in the pathophysiology of parasitic infections. We also discuss how hypoxia modulates host immune responses in the context of protozoan infections.