Introduction: The casirivimab and imdevimab antibody cocktail has proven to be extremely effective against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delta variant. Currently, no data on the clinical outcomes of antibody cocktail with the newer omicron form is available. This retrospective study evaluated the effectiveness of casirivimab and imdevimab antibody cocktail in patients infected with SARS-CoV-2 delta and omicron variants. Methodology: Data of 85 patients of age < 60 years, with comorbid conditions and BMI > 25 kg/m2 were identified from a database of 871 patients. Results: Most of the patients in both delta and omicron groups were administered 600 mg casirivimab + 600 mg imdevimab intravenously. SARS-CoV-2 symptoms started resolving from the 3rd day and by the end of the 14th day most patients in both groups did not report any symptoms. There was no significant difference between delta and omicron group with respect to average symptom onset days, number of hospitalized days post cocktail and number of days post cocktail administration to reverse transcription polymerase chain reaction (RT-PCR) negative status. Forty (58%) patients in the delta group and 16 (94%) patients in the omicron group had the high-resolution computed tomography (HRCT) score of zero. No patient required oxygen support during hospitalization and no mortality was reported. Conclusions: There was no difference in effectiveness and safety of casirivimab and imdevimab antibody cocktail in the patients infected with SARS-CoV-2 delta or omicron.