Background: During the COVID-19 pandemic, mental health disorders and level of stress show a major increase compared to before the pandemic. Coronavirus-related stress is recently the leading cause of negative impacts on global mental health. Thus, maintaining positive mental health is as important as maintaining physical health during COVID-19. The aim of this study was to analyze salivary mental stress biomarkers as cortisol, alpha-amylase, and chromogranin A in hospitalized patients with COVID-19 to compare their potential relationship with stress symptoms., Material and Methods: A total of 80 adult hospitalized patients with moderate COVID-19 disease and a control group ( n = 80) randomly selected were conducted as participants. Saliva cortisol (sCort), saliva alpha-amylase (sAA), and saliva and chromogranin A (sCgA) were determined by the ELISA method (Bio Vendor, USA). Symptoms of stress were measured with a stress symptom checklist (SSCL)., Results: The patients group presented significantly higher levels of sCort, sAA, and sCgA compared with the control group. The correlation analysis showed a positive correlation with strong strength between sCort and sAA ( r = 0.934, p < 0.01), as well as sAA with sCgA ( r = 0.714, p < 0.01). A moderate positive correlation was found between sCort with sCgA ( r = 0.618, p < 0.05). Based on their stress scores from the SSCL the patients were associated with high stress level (30.00%) and very high stress levels (67.5%). In terms of the controls, all the participants showed a low to moderate stress level. We found significant positive correlation between levels of stress and salivary biomarkers., Conclusion: Data from our study demonstrated that salivary biomarkers are promising tools of exploring COVID-19 related stress., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Deneva, Ianakiev and Boykinova.)