Background Sickle cell disease (SCD) is a recessive hereditary condition. The physical changes caused by SCD affect the quality of life (QoL) by negatively impacting psychological aspects. Objective This study aimed to assess the prevalence of depression and anxiety in SCD patients based on different sociodemographic characteristics in Jeddah, Saudi Arabia. Method A cross-sectional study was conducted at King Abdulaziz University Hospital (KAUH) in Jeddah from 13 July to 30 August 2021. The included patients were 18 years of age and above and affected with sickle cell disease. Medical staff interviewed the patients and filled the Patient Health Questionnaire (PHQ)-9 and General Anxiety Disorder (GAD)-7. Result One hundred nineteen (119) patients were included in this study. The median age of participants was 32 and mostly male (n=72, 60.5%). The rate of depression was 45.4%. On the other hand, the rate of anxiety was 22.7%. The median of the PHQ-9 score was 8±8 while the median of the GAD-7 score was 5±8. Moreover, the study showed that anxiety and depression in relation to sociodemographics were higher in the patient age groups of 30-34 years old, male, single, unemployed, and with higher education. There was a significant association between depression rate and the two variables: patient employment status (49.3%; p=0.047) and a family history of SCD (51%). Conclusion Depression in patients with sickle cell disease is prevalent and correlated to demographic and social factors.