Children with sickle cell anaemia (SCA) experience recurrent vaso-occlusive crises and complications with possible impact on their health-related quality of life (HRQoL). This study determined HRQoL of 130 children aged 5-15 years with SCA and compared it to age- and sex-matched apparently healthy haemoglobin AA children in The Gambia. It also determined the impact of SCD severity, and sociodemographic and clinical data on HRQoL. HRQoL was determined using the Pediatric Quality of Life Inventory. SCD severity was assessed with a validated clinico-laboratory scoring system. The mean age of the participants was 9.74 ± 2.81 years, with a male: female ratio of 1.1:1. Underweight (p = 0.019) and stunting (p = 0.045) were more prevalent among children with SCA. Majority, 83.1%, had mild SCD, while 13.1% had moderate SCD and 3.8% had severe SCD. The mean HRQoL scores were significantly lower in SCA than HbAA children in the physical, emotional, social, school and overall health domains, p <0.001. Seventy-five (57.7%) of SCA patients had poor HRQoL. SCD severity scores had significant inverse correlations with HRQoL scores in the emotional (r = - 0.2, p = 0.020) and school (r = -0.18, p = 0.039) domains. Significant pain >3 episodes in the preceding 12 months (OR=1.9; 95% CI = 1.392 - 2.201; p = 0.028); late diagnosis (OR = 1.8; 95% CI = 1.697-1.957; p = 0.012); and clinical stroke (OR = 69.3; 95% CI = 1.337-89.36; p = 0.037) were identified as significant independent predictors of poor overall HRQoL among children with SCA. SCA has a negative impact on all domains of HRQoL. Frequent significant pain crises, late diagnosis and stroke were independent predictors of poor HRQoL in Gambian children with SCA.