In COVID-19, critical disease and invasive mechanical ventilation (IMV) increase the risk of death, mainly in patients over 60 years of age. Objectives: To find the relationship between miR-21-5p and miR-146a-5p in terms of the severity, IMV, and mortality in hospitalized COVID-19 patients younger than 55 years of age. Methods: The patients were stratified according to disease severity using the IDSA/WHO criteria for severe and critical COVID-19 and subclassified into critical non-survivors and critical survivors. Results: Ninety-seven severe/critical COVID-19 patients were included; 81.3% of the deceased were male and 18.8% were female. Higher expression miR-21-5p levels were associated as follows: severe vs. critical disease (p= 0.007, FC = 0.498), PaO2/FiO2index, mild vs. severe (p= 0.027, FC = 0.558), and survivors vs. non-survivors (p= 0.03, FC = 0.463). Moreover, we identified correlations with clinical variables: CRP (rho = −0.54,p< 0.001), D-dimer (rho = −0.47,p< 0.05), related to damage in the kidney (rho = 0.60,p< 0.001), liver (rho = 0.41,p< 0.05), and lung (rho = 0.54,p< 0.001). Finally, miR-21-5p thresholds were calculated according to severity (8.191), IMV (8.191), and mortality (8.237); these values increased the risk of developing a critical disease (OR = 4.19), the need for IMV (OR = 5.63), and death (OR = 6.00). Conclusion: Increased expression levels of miR-21-5p are related to worse outcome of COVID-19 in younger hospitalized patients.