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The study of human neurological infection faces many technical and ethical challenges. While not as common as mammalian models, the use of <i>Drosophila</i> (fruit fly) in the investigation of virus–host dynamics is a powerful research tool. In this review, we focus on the benefits and caveats of using <i>Drosophila</i> as a model for neurological infections and neuroimmunity. Through the examination of in vitro, in vivo and transgenic systems, we highlight select examples to illustrate the use of flies for the study of exogenous and endogenous viruses associated with neurological disease. In each case, phenotypes in <i>Drosophila</i> are compared to those in human conditions. In addition, we discuss antiviral drug screening in flies and how investigating virus–host interactions may lead to novel antiviral drug targets. Together, we highlight standardized and reproducible readouts of fly behaviour, motor function and neurodegeneration that permit an accurate assessment of neurological outcomes for the study of viral infection in fly models. Adoption of <i>Drosophila</i> as a valuable model system for neurological infections has and will continue to guide the discovery of many novel virus–host interactions.