Purpose <p>Post-COVID-19 olfactory dysfunction (PCOD) has been associated with structural brain changes, but the underlying molecular mechanisms and their relationship to gray matter volume (GMV) changes remain unclear.</p> Methods <p>We included 36 patients with PCOD and 40 healthy controls. All patients underwent olfactory psychophysical testing (Sniffin’ Sticks) and a visual analogue scale (VAS) assessment for olfactory function. GMV values for 34 brain regions were extracted, and Spearman’s correlation analysis was performed with olfactory psychophysical testing scores. Partial least squares regression (PLS) was applied to explore the relationship between regional GMV differences and gene expression patterns. Gene set enrichment analysis was performed to identify relevant biological processes and cell types.</p> Results <p>PCOD patients showed increased GMV in the entorhinal cortex (<i>t</i> = 3.065, <i>p</i> = 0.003), positively correlated with the VAS score for olfactory function (<i>r</i> = 0.37, <i>p</i> = 0.028) and Sniffin’ Sticks Test total score (<i>r</i> = 0.37, <i>p</i> = 0.026). PLS analysis identified gene expression patterns that were significantly associated with regional GMV changes. Enrichment analysis revealed that genes linked to GMV changes were enriched for biological processes related to “inorganic ion transmembrane transport” and “regulation of protein transport”. Additionally, these genes were highly expressed in GABAergic neurons.</p> Conclusions <p>These findings provide mechanistic insights into the relationship between altered brain structure and gene expression in PCOD, highlighting the involvement of specific biological pathways and cell types in the pathophysiology of olfactory dysfunction following COVID-19.</p>