African Horse Sickness (AHS) is a vector-borne viral disease of equids. The disease can be highly lethal with mortality rates of up to 90% in non-immune equine populations. The clinical presentation in the equine host varies, but the pathogenesis underlying this variation remains incompletely understood. Various small animal models of AHS have been developed over the years to overcome the financial, bio-safety and logistical constraints of studying the pathology of this disease in the target species. One of the most successful small animal models is based on the use of interferon-alpha gene knock-out (IFNAR−/−) mice. In order to increase our understanding of African Horse Sickness virus (AHSV) pathogenesis, we characterised the pathology lesions of AHSV infection in IFNAR−/− mice using a strain of AHSV serotype 4 (AHSV-4). We found AHSV-4 infection was correlated with lesions in various organs; necrosis in the spleen and lymphoid tissues, inflammatory infiltration in the liver and brain, and pneumonia. Significant viral antigen staining was only detected in the spleen and brain, however. Together these results confirm the value of the IFNAR−/− mouse model for the study of the immuno-biology of AHSV infections in this particular in vivo system, and its usefulness for evaluating protective efficacy of candidate vaccines in preclinical studies.