In the present study, we investigated biochemical, hematological, lipidomic, and metabolomic alterations associated with different SAR-CoV-2 variants of concern (VOCs), such as WT, α, β, γ, and δ, as well as their impact on COVID-19 severity. Across the first and second waves in India, a machine learning approach was used in 3134 COVID-19 patients, and nine critical biochemical and hematological parameters, namely, C-reactive protein (CRP), D-dimer, ferritin, neutrophil, WBC count, lymphocyte, urea, creatine, and lactate dehydrogenase (LDH), were identified. Furthermore, through metabolic and lipidomic profiles of lung and colon cells transfected with spike VOCs, notable dysregulation was exhibited by the delta variant correlated with characteristic pathways such as catecholamine and thyroid hormone synthesis. A corroborating meta-analysis also highlighted the involvement of urea and amino acid metabolism pathways. Overall, our study provides crucial insights into metabolic and biochemical disruptions caused by VOCs, contributing to a better understanding of COVID-19 pathogenesis and the development of targeted interventions.