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Introduction: Coronavirus disease 2019 (COVID-19) was was a global pandemic outbreak that emerged in three waves of varying severity. The inflammatory markers can be used to identify the transition of severity of the disease from a mild to severe or critical illness and also to predict the mortality. To improve clinical outcomes, continuous monitoring of these biomarkers in hospitalised patients is essential. Aim: To compare the serum C-Reactive Protein (CRP), Lactate Dehydrogenase (LDH), serum ferritin and D-Dimer as a predictor of severity and mortality in hospitalised patients in different clinical categories during three waves of COVID-19 . Materials and Methods: This retrospective study was conducted at Vydehi Institute of Medical Sciences and Research Centre, Karnataka. A total of 6189 patient’s data were retrieved from medical record section with confirmed cases of COVID-19 admitted during the three waves of COVID-19. The results of four inflammatory marker on the day of admission were analysed in mild, moderate, severe and critically ill patients and compared with disease severity, survival and death and also assessed the difference between first, second, and third wave of COVID-19 for sensitivity and specificity. Data was analysed by Chi-square test, Mann Whitney U test, ANOVA (Analysis of Variance), and Kruskal Wallis test and Receiver Operating Curve (ROC). Results: The median age of patients in the mild category was found to be younger in all three waves compared to those in the severe and critically ill categories. In terms of gender distribution, males were more prevalent than females. Inflammatory markers were significantly increased in all three waves in the severe and critically ill categories. The median CRP (mg/dL) values were significantly increased in the critically ill in wave three compared to waves one and two. The median values of LDH IU/L significantly increased in critically ill patients in the second wave. The median values of ferritin increased significantly in wave one. The D-dimer values significantly increased in the critically ill category in wave three. Conclusion: Before proceeding on to a specific diagnosis by RT-PCR, a combination of standard laboratory markers (CRP, LDH, and Ferritin D-Dimer) could accurately and reliably predict the diagnosis of COVID-19 with established sensitivity and specificity.