Developing a host-specific antiviral will protect against future pandemics of unknown virus "X" while also being impervious to virus evolution. Our team has demonstrated that Fibrillarin (FBL) inhibition blocks the replication of multiple henipaviruses and related paramyxoviruses without adversely impacting cell viability. FBL is a 2’O-methyltransferase with roles in translation. We have investigated the impact of FBLi on post-transcriptional regulation of both host and viral gene expression during Hendra (HeV) infection. Ribosome profiling was performed using HeLa cells infected with HeV following transfection with siRNAs achieving >90% FBL knockdown. Reads mapping to the HeV genome showed a gradient of transcript abundance 5’ to 3’ due to inefficient re-initiation of paramyxovirus RNA-dependent RNA polymerase. In FBLi cells, decreases in both viral mRNA transcripts and ribosome occupancy were observed for genes towards the 5’ end. Quantitative analysis of ribosome footprint reads revealed a significant decrease in N and P genes with no impact on translation efficiency (i.e., ribosome occupancy relative to mRNA transcript), indicating that FBLi impacts HeV replication prior to ribosome engagement. Given that the HeV virion carries all transcription components necessary for the first round of transcription (i.e., N, P and L proteins), and viral transcripts downstream of N and P are not impacted by FBLi, a block in transcription is unlikely. Rather, we propose that FBLi causes N and P mRNA degradation. To gain insight into the mechanism, we examined host gene translation using ribosome footprints normalised to transcript abundance and found that genes reduced in translation by FBLi were enriched for verified 2’-O-methylation sites, prediction of 2'O-methylation sites using an online tool called i2OM reveals >400 high confidence sites in the Hendra genome. We hypothesize that FBLi leads to hypomethylation of the genome, increased recognition by pathogen recognition receptors and subsequent transcript degradation.