Tick-borne encephalitis (TBE) is a potentially fatal neuroinfection of humans caused by the TBE virus. There is no specific therapy for TBE, as treatment is only supportive. Therefore, efforts to develop an effective specific therapy for TBE are warranted. Small molecule inhibitors and monoclonal antibodies are under intense investigation as potential therapeutics to combat TBE in humans. Here we describe the basic methods that can be used to test small molecule antivirals or monoclonal antibodies against TBEV. These include in vitro methods such as plaque assays, neutralizing assays, immunofluorescence staining of viral antigen, and cell-based antiviral assays, as well as in vivo assays in mouse model of TBE.