Updated project metadata. The altered molecular proteins and pathways in response to COVID-19 infection are still unclear. Here, we performed a comprehensive proteomics-based investigation of of nasopharyngeal swab samples from COVID-19 patients to identify viral and host peptides by employing simple extraction strategies and also established a panel of host proteins using high-resolution mass spectrometry. The differentially expressed peptides/proteins identified from host and pathogen correlated with the viral load of the host which indicates that these proteins might be good prognostic biomarkers of severity prediction. A few host proteins such as Interleukin-6, L-lactate dehydrogenase, C-reactive protein, Ferritin and Aspartate aminotransferase was found to be upregulated in COVID-19 positive patients using targeted MRM study. Further, the proteins L-lactate dehydrogenase, Aspartate aminotransferase and Alanine aminotransferase was also validated in the clinical settings using immunological assays. We also identified neutrophil degranulation, platelet degranulation, interleukin-12 signaling pathways, mRNA translation of proteins and , co-factor metabolomic process protein metabolism, and stress responses to be key GO enriched pathways, thus altered in the COVID-19 infected patients.providing the detailed investigation of host response in COVID-19 infection , thus providing the landscape of COVID-19 pathophysiology. This study thus also revealed that mass spectrometry-based detected host proteins/peptides has a potential for clinical translation and a few proteins might be routinely monitored in clinics for the disease progression, peptide tests can be used by clinicians for diagnosis as well as identified pathways/ markers as the predictors of disease progression. Furthermore, the identified proteins and their drug binding studies might aid in COVID-19 therapeutic interventions.