A growing body of evidence indicates that neutrophil elastase (NE) is involved in the pathogenesis of respiratory infectious diseases, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aimed to analyze the dynamic changes in serum levels of NE associated with inflammation, disease activity, and mortality rate in patients with COVID-19. We measured the serum concentrations of NE, C-Reactive protein (CRP), interleukin (IL)- 4, IL-6, IL-8, IL-10, and vitamin D levels in 83 ICU and 69 non-ICU patients compared with 82 healthy subjects (HS) in three-time points (T1-T3). Serum levels of NE, IL-6, IL-8, and CRP in ICU and non-ICU patients were significantly higher than HS (
P
<0.001) in three-time points. Also, serum levels of NE, IL-6, IL-8, and CRP in ICU patients were significantly higher than in non-ICU patients (
P
<0.05). On the day of admission (T1), the levels of NE, CRP, IL-6, IL-8 were gradually decreased from T1 to T3. At the same time, IL-4 and IL-10 were gradually increased from T1 to T2 and then reduced to T3. Further analyses demonstrated that the levels of NE, IL-6, and IL-8 in deceased patients were significantly higher than in recovered patients (
P
<0.05). The ROC curve analysis demonstrated that markers, including NE, IL-6, and IL-8, were valuable indicators in evaluating the activity of COVID-19. Overall, our results signify the critical role of NE in the pathogenesis of COVID-19, and also, further support that NE has a potential therapeutic target for the attenuation of COVID-19 severity.