To model infection of viruses targeting the liver and the central nervous system, two-dimensional in vitro cultures rapidly show their limitations. Conversely, in vivo models do not easily allow the investigation of early events of the infection process. In between, ex vivo models, comprising mainly organoids and organotypic cultures, mimic or retain the cytoarchitecture of the organ while being relatively simple to handle and analyze. Here, we summarize the main features of brain and liver ex vivo models and pinpoint examples of their utilization for studying encephalitogenic and hepatotropic viruses. We highlight a gap of development and application of liver compared to ex vivo models in virology. Many hepatotropic viruses can also infect and/or have impacts on the central nervous system. In this sense, we sought to present these ex vivo models while providing a conceptual framework for the modeling of the hepatocerebral axis in the context of viral infections.