Millions of people have lost their lives because of the COVID-19 pandemic. Better utilization of healthcare resources would be possible with the help of an early prediction tool for severity and mortality risk. While several biomarkers have been postulated as prognostic markers of COVID-19, including D-dimer, lactate dehydrogenase (LDH), C-reactive protein (CRP), and other recently investigated biomarkers including serum cystatin C and serum calprotectin, their relevance as prognostic markers is still unclear. This study aimed to determine whether or not serum cystatin C and serum calprotectin may be used as predictive tools for estimating disease severity and prognosis. About 95 COVID-19 patients were enrolled in this observational cohort trial between the middle of October 2020 and the beginning of 2021. Serum cystatin C and serum calprotectin levels were estimated serially and compared between severe (NEWS 2 score ≥5) and non-severe (NEWS 2 score <5) groups, survivors and died, and based on comorbidities at each time point. The receiver operating characteristic (ROC) curve was used to determine the best severity and mortality criteria, which were then used in the survival analysis. On day 1, median cystatin C levels were considerably higher in the severe group (P<0.001), in patients with cardiovascular disease (P<0.05), in patients with chronic lung disease (P=0.009), and in patients who died (P<0.05). On day 3, it was still significantly higher in the severe (P<0.05) and dead (P<0.05) groups. Those with chronic lung disease and patients who ultimately passed away had significantly higher serum calprotectin levels (P=0.008 and P<0.05, respectively). Early prognostic and therapeutic decision-making for COVID-19 patients may benefit from using serum cystatin C. A more reliable indicator of critical disease appears to be serum calprotectin.