The Caribbean spiny lobster, Panulirus argus (Latreille, 1804) supports important fisheries in the Caribbean region. This species is affected by a deadly virus, Panulirus argus Virus 1 (PaV1), the only known pathogenic virus for this species. As infection progresses, the effects of PaV1 on its host become systemic, with far reaching impacts on the host's physiology, including structural injuries to its gastrointestinal organs, such as the hepatopancreas and the gut. This last one becomes highly compromised in the last stages of infection. Since the gut is a key organ for the physiological stability of lobsters, we compared the transcriptomic changes in the gut of juvenile individuals of Panulirus argus naturally infected with PaV1. In the RNA-Seq analysis, we obtained a total of 485 × 106 raw reads. After cleaning, reads were de novo assembled into 68,842 transcripts and 50,257 unigenes. The length of unigenes ranged from 201 bp to 28,717 bp, with a N50 length of 2079, and a GC content of 40.61%. In the differential gene expression analysis, we identified a total of 3405 non redundant differential transcripts, of which 1920 were up-regulated and 1485 were down-regulated. We found alterations in transcripts encoding for proteins involved in transcriptional regulation, splicing, postraductional regulation, protein signaling, transmembrane transport, cytoskeletal regulation, and proteolysis, among others. This is the first insight into the transcriptomic regulation of PaV1-P. argus interaction. The information generated can help to unravel the molecular mechanisms that may intervene in the gut during PaV1 infection.