Background <p>Coronavirus disease 2019 (COVID-19) is frequently associated with neurological manifestations, most notably anosmia, raising questions regarding central nervous system involvement. Neuropathological studies have reported heterogeneous findings, and the relative contribution of direct viral neurotropism versus indirect systemic mechanisms remains controversial.</p> Methods <p>An autopsy-based case–control study was conducted including 16 COVID-19–positive decedents and 15 age- and sex-matched COVID-19–negative controls. Histopathological examination focused on the olfactory bulb, olfactory tract, and frontal cortex. Reactive gliosis, microglial activation, perivascular inflammation, microvascular injury, neuronal eosinophilia, and corpora amylacea were assessed using standardized semiquantitative criteria and compared between groups.</p> Results <p>COVID-19–positive cases demonstrated significantly increased reactive gliosis and microglial activation in the olfactory bulb, along with a higher frequency of mild perivascular lymphocytic infiltration in the frontal cortex. In contrast, corpora amylacea and petechial hemorrhages were observed in both COVID-19–positive and control groups, without statistically significant differences. No evidence of viral cytopathic changes or diffuse encephalitis was identified. Systemic pathological findings in COVID-19–positive cases were consistent with severe multisystem disease.</p> Conclusions <p>COVID-19 is associated with region-specific but non-uniform neuropathological alterations dominated by reactive and vascular changes rather than encephalitic processes. The inclusion of a contemporaneous control group demonstrates that several commonly reported histological findings represent nonspecific background changes. These findings support predominantly reactive and vascular mechanisms of CNS involvement in COVID-19 rather than direct encephalitic processes.</p>