A range of neurological symptoms have been reported post severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Similar to other neurotropic viral infections such as herpes simplex virus induced encephalitis and cytomegalovirus‑related congenital conditions, infection‑caused inflammation may contribute to brain injury and long‑term dysfunction. To better define transcriptional dysregulation in the brain in the context of viral infection, we performed spatial transcriptomic analysis on formalin‑fixed, paraffin‑embedded (FFPE) brain tissue from patients who died from COVID‑19, alongside healthy controls. Whole‑section profiling with the GeoMx® Human Whole Transcriptome Atlas (WTA) enabled differential gene expression analysis across grey and white matter, focusing on the pyramids, inferior olivary complex (IOC), and midline regions. The pyramidal and IOC regions showed strong inflammatory activation, with gene expression enriched for hypoxia response and antigen presentation pathways, whereas the midline region displayed a comparatively homeostatic profile. These findings provide new spatial and molecular insights into how SARS‑CoV‑2 infection shapes the neuroimmune landscape and may inform future strategies for brain‑targeted immunotherapies and vaccines to reduce neurological complications of viral infection.