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Coronavirus disease 2019 (COVID-19) is associated with systemic inflammation and immune dysregulation, potentially affecting hypothalamic–pituitary–adrenal (HPA) axis function and glucocorticoid signaling. However, the dynamics and clinical relevance of these alterations across different disease phases remain insufficiently defined. In this cross-sectional observational study, 101 participants were divided into three groups: patients with active COVID-19 (n = 33), individuals ≥ 6 months post-COVID-19 (n = 35), and a reference group of healthy individuals (n = 33). Serum cortisol, circulating glucocorticoid receptor alpha (GRα), and selected cytokines were measured. Statistical analysis included parametric and non-parametric tests, multivariable generalized linear models adjusted for age and sex, correlation analysis, and receiver operating characteristic (ROC) analysis. Lower serum cortisol levels were observed in approximately two-thirds of patients during the acute phase. Circulating GRα concentrations demonstrated a significant gradient across groups, with the lowest levels in active infection and partial restoration post-COVID. Active COVID-19 status remained independently associated with reduced GRα levels after adjustment for age and sex. The cytokine profile, including interleukin-17A (IL-17A), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10), provided a mechanistic context for inflammation-associated modulation of glucocorticoid signaling, most evident during acute infection. Significant correlations between cortisol, GRα, and inflammatory mediators were observed only in this phase. ROC analysis demonstrated a high degree of statistical separation between active COVID-19 and healthy individuals (AUC 0.942; 95% CI: 0.878–1.000). Given the predefined group structure and modest sample size, these findings should be considered exploratory. Overall, the results support the presence of dynamic and potentially reversible immune–endocrine dysregulation during and after SARS-CoV-2 infection. Further validation in larger prospective cohorts is required.