A novel genus within the Orthomyxoviridae family was identified in the USA and named Influenza D virus (IDV). Bovine have been proposed to be the primary host and three main viral lineages (D/OK-like, D/660-like and D/Japan-like) have been described. Experimental infections were so far performed in swine, ferret, calf and guinea pig, in order to study IDV pathogenesis.We developed a murine experimental model to ease the study of IDV pathogenesis and immune response. DBA/2 mice were inoculated with 105 TCID50 of D/bovine/France/5920/2014 (D/OK-like). No clinical signs and weight loss were observed. Viral replication was observed mainly in the upper respiratory tract (nasal turbinates) but also in lower respiratory tract of infected mice, with a peak at 4 days post-infection. Moreover, the virus was also detected in the intestines. All infected mice seroconverted by 14 days post infection. Transcriptomic analyses demonstrated that IDV induced an activation of pro-inflammatory genes such as IFN-γ and CCL2. Inoculation of NFκB-luciferase and Ifnar1-/- mice demonstrated that IDV induced mild inflammation and that type I interferons response was not necessary in IDV clearance. Adaptation of IDV by serial passages in mice was not sufficient to induce disease or increased pathogenesis.Taken together, present data and comparisons with the calf model show that our mouse model allows for the study of IDV replication and fitness (before selected viruses may be inoculated on calves) and also of the immune response.ImportanceInfluenza D virus (IDV), a new genus of Orthomyxoviridae family, presents a large host range and a worldwide circulation. The pathogenicity of this virus has been studied in the calf model. The mouse model is frequently used to enable a first assessment of a pathogen´s fitness, replication and pathogenesis for influenza A and B viruses. We showed that DBA/2 mice are a relevant in vivo model for the study of IDV replication. This model will allow for rapid IDV fitness and replication evaluation and will enable phenotypic comparisons between isolated viruses. It will also allow for a better understanding of the immune response induced after IDV infection.