Background: Sickle cell disease is a genetic disease passed from sick or carrier parents to their children. Raising awareness among individuals and couples planning to marry can reduce the spread of the disease. Objectives: This study aims to determine the knowledge and awareness of Al-Darb governorate residents in the Jazan region towards sickle cell anemia. Methods/Design: A cross-sectional study was conducted in the AlDarb governorate, Jazan region using a close-ended questionnaire. The data was then analyzed with SPSS v.23. Results: Among the 316 valid, collected, and analyzed questionnaires, 76.9% were completed by females, most of whom were students. About 25.6% of the participants had heard about the disease from their families. Additionally, 59% identified stroke and the acute chest syndrome as the most important complications of the disease. Regarding the individuals’ attitudes towards the disease, 95.6% believed that a preventive plan should be followed for infected children. Furthermore, 88% stated that genotype affects their decision to get married. Conclusions: In general, most participants demonstrated an acceptable level of knowledge about sickle cell disease, including its transmission methods and prevention. However, there is a significant need for increased community awareness regarding proper nutrition, addressing misconceptions about the disease, and establishing blood disease centers within the study population. Keywords: sickle cell anemia, knowledge, awareness, AlDarb governorate