Background: In sub-Saharan Africa, sickle cell anemia management heavily relies on blood transfusions, exposing patients to transfusion-transmitted infections (TTIs) such as HBV, HCV, HIV, and syphilis. As patients transition into adolescence, they face severe behavioral risks and a potential cognitive "knowledge-do gap." This study aimed to determine the seroprevalence of TTIs and evaluate Knowledge, Attitudes, and Practices (KAP) dynamics among sickle cell children and adolescents in Mbujimayi, Democratic Republic of the Congo (DRC). Methods: A hospital-based cross-sectional study was conducted in Mbujimayi. Biological screening for HBsAg, anti-HCV, HIV-1/2, and syphilis antibodies was performed using immunochromatographic rapid diagnostic tests (RDTs). Concurrently, a standardized KAP questionnaire was administered to adolescents to assess viral risk awareness, vaccination misconceptions, and behavioral exposure factors. Results: The study revealed a high seroprevalence of TTIs among sickle cell patients in Mbujimayi. Unlike recent data from Kinshasa, a statistically significant linear correlation was established between cumulative transfusion load and viral seropositivity (p < 0.05), highlighting peripheral blood safety vulnerabilities. The KAP assessment unveiled a severe information asymmetry: over 90% awareness regarding HIV/AIDS contrasted with a critical knowledge deficit and vaccine misconceptions regarding HBV and HCV. While general schooling did not influence TTI awareness, targeted clinical education delivered by physicians significantly reduced diagnostic refusal and enhanced peer-education readiness. However, a persistent "knowledge-do gap" was identified, as many adolescents maintained high-risk community and sexual practices despite having theoretical knowledge. Conclusion: Sickle cell patients in Mbujimayi bear a heavy dual burden of genetic illness and iatrogenic viral risk. Addressing this requires upgrading peripheral blood screening technologies, integrating systematic viral testing into clinical guidelines, and deploying clinician-led peer-education strategies to bridge the cognitive-behavioral gap during adolescent transition.