COVID-19 manifests itself in an array of symptoms. While most patients experience very mild-to-moderate symptoms, around one in five patients develop pneumonia coupled with severe respiratory distress. These patients require treatment in the intensive care units (ICU), however, most of the times, it leads to multi-organ dysfunction and death. Mass spectrometry based proteomics can help us to identify the precise pathophysiological pathways that get perturbed during the course of the disease. Our study involved a comprehensive proteome-wide investigation of COVID negative (n=20), non-severe (n= 18) and severe (n= 36) COVID-19 patients plasma samples. We categorized patients into severe and non-severe groups and conducted LFQ based discovery proteomics for unraveling differentially expressed proteins followed by pathway enrichment studies and validation of targets by targeted studies on a batch of longitudinal samples.