COVID-19 has produced more than 176 million infected individuals and almost 3.2 million deaths worldwide. The infection results in a dysregulated systemic inflammation, multi-organ dysfunction, and critical illness. Cells of the central nervous system (CNS) are also affected triggering a dysregulated neuroinflammatory response.Low doses of glucocorticoids (GCs) orally or intravenously administered has been proved to reduce mortality of moderate and severe COVID-19 patients. However, low doses administered by those routes do not reach therapeutic levels in the CNS. In contrast, if dexamethasone is administered by the intranasal route can result in therapeutic doses in the CNS even at low doses of the GC. Methods: This is an approved multicentric randomized controlled protocol to compare the effectiveness of low doses of intranasal dexamethasone versus intravenous administered in adult moderate and severe COVID-19 patients. The protocol is conducted in five health institutions in Mexico City. A total of 120 patients will be randomized in two groups (intravenous vs intranasal) at 1:1 ratio, both groups will be treated with these dexamethasone schemes for 10 days. The primary outcome of the study will be clinical improvement, defined as a statistically significant higher reduction in the NEWS-2 score in intranasally versus intravenously dexamethasone treated patients. The second outcome will be the reduction in mortality during hospitalization. Conclusions: This protocol is currently undertaken to improve the efficacy of the standard therapeutic dexamethasone regimen for moderate and severe COVID-19 patients. Trial registration: ClinicalTrials.gov identifier: NCT04513184 Registered November 12, 2020 and was approved by COFEPRIS with identifier DI/20/407/04/36. People are currently being recruited.