Pakistan has a high prevalence of viral hepatitis andthese transfusion-transmitted illnesses (TTIs) pose a major hazard to the health of patients who need blood transfusions, which has a negative impact on the affordability and accessibility of safe blood products in underfunded or less strengthened healthcare systems. While selecting a donor for blood donation, he/she must be healthy enough to donate 500 mL of whole blood, but some of them who were considered the healthiest community were caught to be reactive while getting screened for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV), which reflects the true prevalence of these illnesses in this specific population. To study the seroprevalence and trends of HBV, HCV, and HIV in healthy blood donors of Sindh, Pakistan. Blood donated by healthy donors from Sindh, collected from January 2018 to December 2022, was tested by enzyme-linked immunosorbent assay (ELISA) or chemiluminescent immunoassay (CLIA) at 185 blood centers running under the umbrella of Sindh Blood Transfusion Authority Pakistan (SBTA). The results of serological screening tests for HBV, HCV, and HIV performed from January 2018 to December 2022revealed a continuously increasing trend of all infections. The total number of blood donations in the blood banks across the province showed a progressive increase from 22,822 donors in 2018 to 937,039 donors in 2022, which is 14.21% of the total increase. Among 4,199,195 donors screened from the said period, 3,821,268 (91%) were replacement donors while only 3,77,927 (9%) were voluntary donors. Among them 3,870,598 (92.2%) were males and only 3,285,97 (7.8%) were females, whereas with regardto donors' age, most of them i.e. 2,664,648 (63%), fallin the 29-39 years age group. Overall, from 2018 to 2022, out of a total of 4,199,195 individuals screened, 81,266 (1.94%) tested positive for HCV, 71,688 (1.7%) tested positive for HBV, and 6,711 (0.15%) tested positive for HIV. The total number of positive cases across all three infections was 159,665 (3.80%). The overall average seroprevalence of hepatitis B surface antigen (HBsAg), anti-HCV, and anti-HIV among blood donors of 185 blood banks, for five years, was 2.78%, 3.82%, 3.65%, 4.15%, and 4.04%, respectively. The study highlights a concerning increase in the prevalence of HCV, HBV, and HIV among blood donors in Sindh, Pakistan, over the five-year period. It underscores the importance of continued surveillance, prevention, and intervention strategies to address these infections. The recommendations include the promotion of voluntary blood donors and screening of donated blood through a highly sensitive screening assay (nucleic acid testing). There should be centralized blood collection systems having better personnel and equipment, and non-remunerated voluntary blood donations must be strongly encouraged. All these, however, requirestrong political commitment and multisector engagement with comprehensive policy implementation.