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Background Sickle cell anemia (SCA) is a common condition of public health concern in Nigeria. Different therapeutic approaches have been developed to manage SCA, including blood transfusion. In a bid to develop a sustainable solution to the blood supply pool, the SmileBuilders Initiative organizes a blood donation drive (Donate-A-Pint Project) quarterly in Ibadan, Nigeria. This study aimed to assess the awareness, knowledge, and attitudes of blood donors in Ibadan, Nigeria, towards SCA. Methods A descriptive cross-sectional study was conducted at the University College Hospital Blood Bank in Ibadan over a period of three months. A validated questionnaire, based on similar studies in Nigeria, was used to collect data from blood donors. The SPSS version 23 was used for data analysis, and the chi-square test of independence assessed associations between variables, with a significance level of 0.05. Results Among 205 donors, 68.8% were male, and 42.4% were in the age category of ≥25 years. Most donors (60.0%) were university students. While 12.3% had never heard of SCA, 79.5% were aware of their genotype. Regarding the intrauterine diagnosis of hemoglobin SS (HbSS), 20.0% would allow pregnancy, 31.7% would abort, and 48.3% were undecided. Most respondents (73.2%) had good knowledge of SCA (mean score = 7.0/10.0). If partners were found to have SCA after marriage, 42.9% were undecided. Knowledge of SCA was significantly associated with sex (p = 0.017) and education level (p = 0.001). Conclusion Blood donors in Ibadan have good knowledge, awareness, and attitudes toward SCA. However, more health education would benefit the population., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The University of Ibadan and University College Hospital Research Ethics Committee (UI/UCH REC) issued approval UI/EC/22/0368. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Amusat et al.)