Introduction Multiple variants of SARS-CoV-2 from Alpha to Omicron have an estimated 6.1 million deaths globally till date. However, variants have been found to vary in transmissibility and severity. The present study deals with comparison of morbidity and mortality with SARS-CoV-2 Omicron (B.1.1.529) and Delta (B.1.617.2) variants. Methods An observational retrospective cohort study was conducted on a cohort of laboratory confirmed patients of SARS-CoV-2 diagnosed by qRT-PCR of nasopharyngeal swabs in periods; April-2021 & January-2022; that were sequenced and variants were recorded. Patients were invited for a telephonic interview after voluntary and informed consent was obtained from each participant wherein, the demographics, co-morbidities, oxygen requirement and mortality outcomes of the patients were enquired about. Results A total of 200 patients, with 100 from each period were included in the study. Major comorbidities in patients included hypertension, diabetes mellitus and pulmonary disease. Patients who succumbed to the Delta variant (26%) were higher as compared to the Omicron variant (10%); with the elderly (68 ± 9.7 years) having mortality during the Omicron variant. A significantly increased risk for mortality was observed in comorbidities in both Delta and Omicron variants with hypertension (OR:1.3;5.44), diabetes mellitus (OR:0.99;1.94), chronic pulmonary disease (OR:1.6;2.25), chronic kidney disease (OR:3.18;0.89), and smoking (OR:1.74;1.55). Conclusion The study concluded that the Omicron has potential of high transmissibility and milder disease for the population by large, however, it is not a milder strain for patients with comorbidities having a higher risk of adverse outcomes than that of the previously dominant Delta variant.