Sickle cell disease (SCD) is recognized as a hereditary hemoglobinopathy that is more prevalent due to consanguinity. Assessing knowledge and attitudes toward SCD and premarital screening is crucial to reducing its incidence in Saudi Arabia. The primary objective of this study is to assess the level of awareness and attitudes among the Saudi population regarding sickle cell disease (SCD) and premarital screening. This cross-sectional study among Saudi population, aged between 18 and 60 years old. The questionnaire included demographic features, knowledge statements, and attitude statements. Scores were categorized as high, medium, or low for knowledge and positive, neutral, or negative for attitude. The data was entered using the "Microsoft Office Excel Software" program and then transmitted to the SPSS application, version 20. The study included 789 participants, the majority of participants fall within the 20-30 age range, accounting for 28% of the total. 54.4% of the participants are female, while 45.6% are male. Only 10% of participants had good knowledge scores regarding sickle cell disease and premarital screening, 74.9% had moderate knowledge scores, and 15.1% had poor knowledge scores. As for attitude, only 34.7% of participants had positive attitude scores regarding sickle cell disease and premarital screening. In conclusion, participants show inadequate knowledge and negative attitudes towards sickle cell disease compared to previous figures in Saudi Arabia and worldwide. Addressing the knowledge and attitude levels regarding sickle cell disease and premarital screening in Saudi Arabia is crucial for improving the health and well-being of the population.