Bats are reservoirs for many highly-pathogenic viruses, yet they seem to resist viral disease commonly seen in humans. One of the first defenses against viral infection is the interferon (IFN) response, which leads to expression of protective interferon-stimulated genes (ISGs). Whether bats express unique ISGs that contribute to their viral resistance is unclear. We used RNA-Seq to monitor ISG expression levels in cells derived from the bat Pteropus alecto (black flying fox). We identified over 100 transcripts that are upregulated in response to IFNα, including classical ISGs, long non-coding RNAs, and a small subset of novel ISGs. Kinetic analysis revealed that most bat ISGs can be grouped into two temporal subclusters based on their expression patterns. The first subcluster seems to be conserved in human A549 cells. In the second subcluster, genes from both unstimulated and IFN-treated bat cells were expressed at higher levels than in human cells. In addition, human ISGs in the second subcluster were induced earlier and remained elevated for longer periods than the corresponding bat ISGs. Finally, we identified 2-5A-dependent ribonuclease (RNASEL) as a unique ISG in bat, but not human, cell lines. Activation of bat RNASEL with poly(I:C) led to ribosomal RNA degradation that was increased upon IFN stimulation and decreased in bat cell lines that were targeted for RNASEL knockout by CRISPR-Cas9. RNASEL knockout cells also showed an increased susceptibility to yellow fever virus infection, suggesting bat RNASEL may be important in limiting viral infection. Together, these data suggest the IFN response in bats has both conserved and unique properties that may contribute to specialized immune control of viral infection.