The COVID-19 pandemic caused by the new SARS-CoV-2 coronavirus is the most recent and well-known outbreak of a coronavirus. RNase 1 is a small endogenous antimicrobial polypeptide that possesses antiviral activity against viral diseases. In this study, we investigated a potential association between ribonuclease 1 and the outcome in COVID-19 patients and the impact of increased and decreased RNase 1 levels serum during the course of the disease. Therefore, two patient populations, Cohort A (n = 35) and B (n = 80), were subclassified into two groups, in which the RNase 1 concentration increased or decreased from time point one to time point two. We show that the RNase 1 serum levels significantly increased in the increasing group of both cohorts (p = 0.0171; p < 0.0001). We detect that patients in the increasing group who died had significantly higher RNase 1 serum levels at both time points in Cohort A (p = 0.0170; p = 0.0393) and Cohort B (p = 0.0253; p = 0.0034) than patients who survived. Additionally, we measured a significant correlation of RNase 1 serum levels with serum creatinine as well as creatinine clearance in the increasing and decreasing group at both time points of Cohort A. Based on these results, there is now good evidence that RNase 1 may play a role in renal dysfunction associated with ICU COVID-19 patients and that increasing RNase 1 serum level may be a potential biomarker to predict outcome in COVID-19 patients.