Bat-borne viruses including the severe acute respiratory syndrome coronavirus and Nipah virus generally cause highly pathogenic diseases in humans but not in their bat reservoirs. Nelson Bay orthoreovirus (NBV), a bat-borne virus associated with acute respiratory tract infections in humans, possesses two unique nonstructural proteins, FAST and p17. FAST enhances viral replication through its cell–cell fusion activity, while the function of p17 in the viral life cycle is poorly understood. In this study, we show that p17 is non-essential for viral replication in several human and animal cell lines and does not play a critical role in pathogenesis in vivo . However, p17 localizes to the nucleus and regulates viral replication specifically in cells derived from bats by enhancing the cell–cell fusion activity of FAST in a host-specific manner. Furthermore, the expression of NBV p17 or an NBV p17 homologue from another bat-borne orthoreovirus enhanced the replication of an NBV mutant deficient in p17 in bat cells, suggesting that the function of p17 is virus species-specific. These findings will contribute to our understanding of how the replication of viruses is regulated in their natural reservoirs.