Trypanosoma cruzi, the causative agent of Chagas’ disease, invades the central nervous system where it multiplies inside glial cells and neurons and yet, contrary to most other brain infections, it produces little or no tissue damage and symptoms. The molecular basis for this apparent paradox remains unknown but it may be that T. cruzi itself actively promotes neuroprotective mechanisms. Here we demonstrate that cultured neuronal cells infected with T. cruzi upregulate survival pathways and resist the deleterious effects of the mitochondrial toxin 3‐nitropropionic acid (3‐NP). In vivo 3‐NP induces Huntington's disease‐like striatal pathology and motor disorders, but these abnormalities develop to a much lesser extent or not at all in mice infected with T. cruzi. What's more, intranasal administration of parasite‐derived neurotrophic factor (PDNF), a T. cruzi surface protein normally shed into the extracellular milieu, reproduces neuroprotective responses and motor disorder prevention of the infection. These results suggest a unique symbiotic‐type mechanism in T. cruzi invasion of the nervous system and, additionally, a novel therapeutic strategy for Huntington's disease. (Supported by NIH NS40574 and NS429660)