Multiple variants of SARS-CoV-2 from Alpha to Omicron have an estimated 6.1 million deaths globally till date. These 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. 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 and 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. 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 significant mortality during the Omicron variant. The mortality was increased in patients with comorbidities as with hypertension (53.8%, 70%), diabetes mellitus (26.9%, 40%), chronic pulmonary disease (30.8%, 20%), and smoking (15.4%, 40%) in the patients infected with both Delta and Omicron variants, respectively. The study concluded that the newer strains of SARS-CoV-2 have potential of high transmissibility and milder disease for the population by large, however, for patients with comorbidities have a higher proportion of adverse outcomes, irrespective of the variant.