How well mouse models recapitulate the transcriptional profiles seen in humans remains debatable, with both conservation and diversity identified in various settings. Herein we use RNA-Seq data and bioinformatics approaches to analyze the transcriptional responses in SARS-CoV-2 infected lungs, comparing 4 human studies with the widely used K18-hACE2 mouse model, a model where hACE2 is expressed from the mouse ACE2 promoter, and a model that uses a mouse adapted virus and wild-type mice. Overlap of single copy orthologue differentially expressed genes (scoDEGs) between human and mouse studies was generally poor (≈15–35%). Rather than being associated with batch, sample treatment, viral load, lung damage or mouse model, the poor overlaps were primarily due to scoDEG expression differences between species. Importantly, analyses of immune signatures and inflammatory pathways illustrated highly significant concordances between species. As immunity and immunopathology are the focus of most studies, these mouse models can thus be viewed as representative and relevant models of COVID-19. Author summary: Herein we used RNA-Seq data and bioinformatics to address how faithfully mouse models of COVID-19 recapitulate human transcriptional profiles. Significant gene expression changes seen during SARS-CoV-2 infection of mouse lungs in 3 mouse models did not show good overlap with significant gene expression changes seen during SARS-CoV-2 infection of human lungs. However, highly significant levels of concordance were seen between species when immune signatures and inflammatory pathways were compared. At the immune and inflammation pathway levels, the mouse models thus emerge as representative and relevant models of COVID-19. [ABSTRACT FROM AUTHOR]