The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has revealed a complex interplay between respiratory and neurological manifestations. This study utilized K18-hACE2 transgenic mice to investigate the morphological, ultrastructural, and transcriptomic changes induced by SARS-CoV-2 infection in both lungs and brain tissues. Histopathological analysis at seven days post-infection revealed significant pulmonary damage characterized by interstitial pneumonia, alveolar septal thickening, with a marked inflammatory infiltrate predominantly consisting of neutrophils and lymphocytes, and an abnormal profile of type II pneumocytes. Concurrently, in the brain, we observed vasculitis, gliosis, and edema, indicating an inflammatory response and vascular compromise that can disturb the blood–brain barrier. In addition, gene expression in lung tissue presented increased CCL2, IL10, and GDDA45D in infected mice and the downregulation of proinflammatory genes. However, in brain tissue, the increased expression of CCL2, CASP1, IL6, IFNB1, and GDDA45G inflammatory genes was observed in infected K18-hACE2 mice.