Introduction: Sickle cell disease is a common genetic disorder in Sub-Saharan Africa, frequently associated with impaired growth and malnutrition in children. Objective: To compare the nutritional status and growth profile of children with homozygous sickle cell disease (HbSS) and healthy controls in Mbujimayi. Methods: A prospective, comparative, analytical study was conducted from November 2025 to March 2026. Seventy-one HbSS children and 69 age- and sex-matched controls (12 months–10 years) were included. Nutritional status was assessed using WHO anthropometric standards. Statistical analysis included Chi-square test, Student’s t-test, odds ratios, and relative risks (p < 0.05). Results: Malnutrition and stunting were significantly higher in HbSS children compared with controls (59% vs 1%, p < 0.001). Sickle cell disease was associated with an increased risk of malnutrition (RR = 3.28; 95% CI: 2.40–4.44). Conclusion: Children with sickle cell disease present significantly impaired nutritional status, emphasizing the need for early nutritional assessment and targeted interventions.