Background Blood transfusion services are vital in healthcare, ensuring a steady and safe supply of blood for patients in need. Identifying seropositive blood donors and understanding their response patterns and behaviors are critical for improving the safety and efficacy of blood transfusion practices. Aim Our study aims to determine the response rate and pattern of blood donors who test reactive for transfusion-transmitted infections (TTIs) and to understand the attitudes of reactive blood donors toward post-donation notification, follow-up, and counseling. Materials and methods Our study is retrospective audit analyzing the data record for a period of 24 months from October 2021 to October 2023 in the transfusion medicine department of a tertiary care hospital in southern India. All donations were screened for hepatitis B, hepatitis C, HIV, malaria, and syphilis. Results Of the total 8,276 donations during the study period, 117 (1.41%) were reactive for various TTIs. The highest prevalence was hepatitis B (0.61%), followed by hepatitis C (0.38%), then HIV (0.22%) and syphilis (0.14%). Of all the TTI reactive donors, 82 donors (70%) responded after communication, and the remaining 30% could not be contacted by any mode of communication. The most common reason for non-communication was the fabricated postal address given by the donors. Of the donors approached, 57 (48.7%) reinstated to our blood bank for further counseling and specific treatment. The donor's busy schedule and out-of-city residence were the main reasons for non-compliance with the follow-up protocol. Conclusion Informing donors of their serological status and providing post-donation counseling are crucial elements of blood transfusion protocol. Necessary knowledge about TTIs are to be instilled to the donors during the blood collection procedure. Moreover, its crucial for the donor to provide accurate demographic details aiding follow up and easy access during times of managing blood inventory.