Background: To win the ongoing battle against the emerging coronavirus, new strategies are needed for reliable diagnosis and more effective treatment, which requires a better understanding of disease biology. This study aimed to determine the changes in Substance P (SP), and Calcitonin Gene-Related Peptide (CGRP) serum levels as a result of SARS-COV-2infection, and to correlate these changes with the pathophysiological events affecting the severity of the disease. Patients and Methods: Serum levels of SP and CGRP were measured for 20 healthy volunteers assigned as controls, and 64 COVID-19-positive patients, subdivided according to disease severity, into 3 groups assigned as asymptomatic (n = 19), hospitalized (n = 24), and ICU admitted (n = 21) groups. The results were statistically compared between the studied groups. Results: The serum levels of SP were significantly elevated in COVID-19 patients (P<0.001) when compared to the control samples, with significant increases between COVID-19 groups due to disease severity. On the other hand, serum levels of CGRP in COVID-19 patients, were greatly decreased (P<0.001) as compared to normal controls, with no effect driven by disease severity Conclusion: SP and/or CGRP can be measured as diagnostic and prognostic biomarkers in SARS-COV-2 infection. Adjusting CGRP level in COVID-19 patients is very important for proper angiogenesis, powerful immune response, and good epithelial repair, so may represent a novel therapeutic approach. Also, targeting NK-1Rs or TRPV-1, could modulate the inflammatory and immune responses in COVID-19, leading to better disease outcomes.