C-reactive protein (CRP) has been one of the most investigated inflammatory-biomarkers during the ongoing COVID-19 pandemics caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The severe outcome among patients with SARS-CoV-2 infection is closely related to the cytokine storm and the hyperinflammation responsible for the acute respiratory distress syndrome and multiple organ failure. It still remains a challenge to determine which of the hyperinflammatory biomarkers and cytokines are the best predictors for disease severity and mortality in COVID-19 patients. Therefore, we evaluated and compared the outcome prediction efficiencies between CRP, the recently reported inflammatory modulators (suPAR, sTREM-1, HGF), and the classical biomarkers (MCP-1, IL-1β, IL-6, NLR, PLR, ESR, ferritin, fibrinogen, and LDH) in patients confirmed with SARS-CoV-2 infection at hospital admission. Notably, patients with severe disease had higher serum levels of CRP, suPAR, sTREM-1, HGF and classical biomarkers compared to the mild and moderate cases. Our data also identified CRP, among all investigated analytes, to best discriminate between severe and non-severe forms of disease, while LDH, sTREM-1 and HGF proved to be excellent mortality predictors in COVID-19 patients. Importantly, suPAR emerged as a key molecule in characterizing the Delta variant infections.