Neuropathogenesis is a feature of Neospora caninum infection. In order to explore this in the absence of acquired host immunity to the parasite, we have tested infection in locusts (Schistocerca gregaria). We show for the first time that locusts are permissive to intra-hemocoel infection with N. caninum tachyzoites. This was characterized by alteration in body weight, fecal output, hemoparasitemia, and sickness-related behavior. Infected locusts exhibited progressive signs of sickness leading to mortality. Also, N. caninum showed neuropathogenic affinity, induced histological changes in the brain and was able to replicate in the brain of infected locusts. Fatty acid (FA) profiling analysis of the brains by gas chromatography and multi-variate prediction models discriminated with high accuracy (98%) between the FA profiles of the infected and control locusts. DNA microarray gene expression profiling distinguished infected from control S. gregaria brain tissues on the basis of distinct differentially-expressed genes. These data indicate that locusts are permissible to infection with N. caninum and that the parasite retains its tropism for neural tissues in the invertebrate host. Locusts may facilitate preclinical testing of interventional strategies to inhibit the growth of N. caninum tachyzoites. Further studies on how N. caninum brings about changes in locust brain tissue are now warranted.