Objectives: The phenotyping of Rh and Kell antigens plays a major role in preventing alloimmunization and adverse events in multi-transfused patients. This study tries to highlight the frequency of Rh and Kell antigens among the blood donors who donated blood at a tertiary care center located in Eastern India. Material and Methods: The study was conducted in the Department of Transfusion Medicine and Blood Bank of All India Institute of Medical Sciences, Patna, from January 2021 to March 2023 on 10,032 whole blood donors of blood groups A, B, O, and AB by column agglutination technique using gel cards for blood grouping and phenotyping. Results: A total of 10,032 whole blood donors of groups A, B, O, and AB were included in the study. The frequency of “D” antigen was 95.77% (n = 9,608), “C” was 90.47% (n = 9,076), “c” was 50.47% (n = 5,063), “E” was 15.9% (n = 1,595), “e” was 99% (n = 9,932), and “K” was 2.67% (n = 268). “c” antigen frequency was 45.81–49.48% in RhD positive blood groups and 100% in all the RhD negative blood groups while “C” antigen frequency was 92.04–94.68% in RhD positive blood groups, and 4–24.13% in RhD negative blood groups. Conclusion: Since pre-transfusion phenotyping in multi-transfusion patients is not routinely practiced, transfusion of at least Rh and Kell phenotyped donor red cells can lead to a great decrease in the risk of alloimmunization and adverse events related to transfusion.