A BSTRACT Background: In this study, we look at the role of nurses in dealing with sickle cell disease (SCD) patients in Jazan city. Objectives: The aim of this study was to determine the knowledge of nurses and their attitudes toward SCD patients in Jazan hospitals, Saudi Arabia. Materials and Methods: In this cross-sectional, hospital-based study, based on the inclusion and exclusion criteria, we recruited 240 nurses from Prince Mohammed bin Nasser and Jazan general hospitals in Jazan city, Saudi Arabia. We depend on the validity and reliability of the instrument that were done by the author who prepared the tool of the primary research, and data management processing was incorporated. Statistical analysis was performed with the obtained data. Results: In this study, 24.2% of males and 75.8% of females were included. Of these, 40.4% of nurses between 35 and 40 years of age. About 50.4% has 10–15 years of working experience. 5% of the study participants’ salary is equal to 5000 SR which is the lower salary in the group of the participants. Also, 54.6% of nurses had a bachelor’s degree, 32.9% had a diploma, and only 12.5% had a master’s degree. Approximately 65% of nurses were married. Around 52% of nurses knew that SCD patients should have daily intake of 3 l of liquid and 44% of them recommended pop, juice, and broth. Among the sociodemographic variables, gender and income source were associated with attitude and knowledge scales, whereas among nurses’ groups, only marital status was associated ( P < 0.05). Also, among the sociodemographic variables of nurses, There is statistically significant relation between the nurses’ knowledge and attitude and the demographic characteristics such as income levels, marital status and experiences as revealed by P.vale <0.05. In this study, 72.5% of nurses had poor knowledge score levels and 27.5% had good knowledge. Conclusion: This study concludes that the average total knowledge score was 8.41 and only 27.5% of nurses had good knowledge about SCD in Jazan region. This study also suggests increasing educational interventions, which could aid in improving nurses’ knowledge and attitudes toward SCD. It is recommended to conduct a similar study with a large number of professionals in order to generalize the findings.