Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for coronavirus disease 2019 (COVID-19). Beyond acute respiratory distress, mild SARS-CoV-2 infection can also result in neural inflammation and dysregulation of neurons and glial cells, ultimately leading to neural circuit dysfunction and cognitive impairment. Oxidized derivatives of cholesterol (oxysterols) drive inflammation during SARS-CoV-2 infection. Pharmacological antagonism of oxysterol receptor Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2 or Gpr183) attenuates infection severity and viral load in the mouse lungs. Oligodendrocytes and their immature precursors (OPCs) express Gpr183 receptors as well as angiotensin converting enzyme 2 (ACE2) receptor used by SARS-CoV-2 to invade host cells, conferring OPCs an extra vulnerability to SARS-CoV-2 infection. This project investigates the impact of SARS-CoV-2 infection in oligodendrocyte lineage cells using Gpr183^-/- mice and wildtype controls that received intranasal SARS-CoV-2 infection. Immunohistochemistry and proteomics analysis showed myelin proteins in the mouse cortex were unaffected by Gpr183^-/-. However, differential gene expression and pathway analysis revealed alteration in synaptic network pathways of Gpr183^-/- mice, highlighting oxysterol signalling involvement in synaptic communication. Immunohistochemistry to detect oligodendrocyte lineage cells 4 days post SARS-CoV-2 infection uncovered an OPC (Pdgfrα⁺) cell density increase by 11.3% in the motor cortex that could be rescued by Gpr183^-/-. Meanwhile, the density of mature oligodendrocytes (ASPA⁺) was unaffected by SARS-CoV-2 infection or Gpr183^-/-. Altogether, these data highlight the impact of SARS-CoV-2 infection in oligodendrocyte lineage cells and a possible mechanism of brain protection against viral infection.