MicroRNAs (miRNAs) contribute to post-transcriptional modulation of the host response during influenza A virus (IAV) infection and may be involved in shaping disease severity. Differential disease severity was achieved in two groups of pigs by immunization of one group with a commercial swine IAV vaccine prior to heterologous IAV (H1N2) challenge of both groups. Lung tissue was harvested 1, 3, and 14 days after challenge and miRNA expression was quantified. Gene Ontology term enrichment analysis was employed to examine the functional relevance of genes potentially regulated by differentially expressed miRNAs in pigs with varying degrees of disease severity following IAV infection. Results suggested that the miRNA response associated with less severe disease may modulate host mechanisms essential for viral life cycle, e.g. transcription, translation, and protein trafficking. During more severe disease, miRNA-mediated regulation may focus on dampening virus-specific processes e.g. virion assembly and viral protein processing, and controlling host metabolism.