Trichomonas vaginalis is a commonly acquired sexually transmitted infection (STI) often found in symbiosis with the intracellular bacterium Mycoplasma hominis, an opportunistic pathogen of the female reproductive tract associated with bacterial vaginosis. How this symbiosis affects infection outcomes, and the host cell innate immune response is still poorly understood. Here we show that T. vaginalis extracellular vesicles down-regulate a non-canonical type I interferon, interferon-epsilon, and suppress type I interferon responses. Transcriptomic analysis reveals that infection with T. vaginalis in symbiosis with M. hominis or M. hominis alone upregulates genes involved in the type I IFN response, but infection with T. vaginalis alone does not. Finally, we show that interferon-epsilon stimulation is protective against T. vaginalis cytoadherence and cytolysis of host cells and increases the ability of neutrophils to kill the parasite. These studies provide insight into the innate immune response induced by a highly prevalent STI and its bacterial symbiont.