Coxiella burnetii is the causative agent of Q fever, a zoonotic disease that threatens both human and animal health. Due to the paucity of experimental animal models, little is known about how host factors interface with bacterial components and affect pathogenesis. Here we used Drosophila melanogaster, in conjunction with the BSL2 Nine Mile phase II (NMII) clone 4 strain of C. burnetii, as a model to investigate host and bacterial components implicated in infection. We demonstrated that adult Drosophila are susceptible to infection with NMII clone 4 and that this bacterial strain, which activates the IMD pathway, is able to replicate and cause mortality in the animals. We show that in the absence of Eiger, the only known tumor necrosis factor (TNF) superfamily homolog in Drosophila, Coxiella-infected flies exhibit reduced mortality to infection. We also demonstrated that the Coxiella type 4 secretion system (T4SS) is critical for the formation of the Coxiella-containing vacuole and an establishment of infection in Drosophila. Altogether, our data revealed that the Drosophila TNF homolog Eiger and the Coxiella T4SS are implicated in the pathogenesis of C. burnetii NMII clone 4 in flies. The Drosophila/NMII clone 4 model mimics relevant aspects of the infection in mammals, such as a critical role of host TNF and the bacterial T4SS in pathogenesis. Our work also demonstrates the usefulness of this BSL2 model to investigate both host and Coxiella components implicated in infection.