ABSTRACT Introduction Sickle cell disease is a chronic hematologic disorder associated with significant physical and psychological challenges, including depression. Children with SCD experience recurrent pain crises, hospitalizations, and social limitations, which can contribute to mental health issues. This study aimed to determine the prevalence of depression and associated factors among school-age children with SCD at Jinja Regional Referral Hospital (JRRH), Eastern Uganda. Methods A cross-sectional study was conducted among 200 randomly selected children aged 6–12 years receiving care at JRRH. Depression was assessed using the Children’s Depression Inventory (CDI). We assessed the association between depression and several factors including sociodemographic characteristics, clinical factors and health related quality of life. Multivariate logistic regression was used to identify factors that were statistically significantly associated with depression at a 95% confidence interval. Results Majority of the participants 55.5% (111/200) were female, 49.5% (99/200) were in pre-primary with a mean age of 6.7 (SD±1.4) years -The prevalence of depression among children with SCD was 43% (95% CI= 40-46%). Among these, 27.9% had mild depression, 58.1% had moderate depression, and 14.0% had severe depression. Factors significantly associated with depression included lack of assured income among caregivers (AOR=3.67, 95% CI=1.35-7.56, p=0.001), having more than one sibling with SCD (AOR=2.54, 95% CI=1.45-4.72, p=0.02), frequent hospital admissions (AOR=2.12, 95% CI=1.56-4.39, p=0.01), and frequent pain crises (AOR=2.10, 95% CI=1.56-4.67, p<0.001). Conclusion Depression is prevalent among children with SCD at JRRH, with socio-economic status of the caregiver, number of siblings with SCD, health facility admission frequency and frequent pain crises playing significant roles. Improving access to financial and social support for caregivers and ensuring adequate pain management are recommended.