Abstract Introduction Sickle cell anaemia (SCA) often presents in early childhood with repeated vaso-occlusive crisis that leads to ischaemia, infarction and fibrosis which may result in a reduction in expected testicular volume (TV) at puberty. Method This was a cross-sectional study of 95 children with SCA aged 1–18 years compared with 95 age-matched controls. Participants responded to an interviewer-administered questionnaire, with their anthropometric measurements taken, pubertal maturity assessed by Tanner staging and testicular ultrasonography done. Changes in TV across the ages were compared graphically and regression analyses were used to determine the factors independently associated with TV. A p-value of <0.05 was considered statistically significant. Results In the prepubertal period, the haemoglobin SS (HbSS) participants had larger median ultrasound TV (MUSTV) compared to the haemoglobin AA (HbAA) controls (p = 0.001). This trend reversed in the pubertal period. On regression analysis, the frequency of testicular pain (p = 0.04), weight (p = 0.02) and pubic hair rating (p = 0.03) of the HbSS participants were significant predictors of increased TVs in the HbSS participants, irrespective of pubertal status. Conclusion The prepubertal MUSTV of the HbSS participants were higher than those of the HbAA controls, while the HbAA controls had higher MUSTV at puberty and beyond. The frequency of testicular pain episodes, pubic hair rating and weight were independent predictors of TV changes in the HbSS participants. Prevention of repeated vaso-occlusive crisis in the prepubertal period may help prevent the reduction in TV and possible hypogonadism. Lay summary Sickle cell anaemia (SCA) causes repeated episodes of painful crisis and in boys, these may affect the way their testes grow. The study set out to document testicular sizes on a one-time basis in boys aged 1–18 years with SCA compared with controls of similar ages. The participants responded to structured questions assisted by the researchers and their body measurements were appropriately taken. Their level of sexual maturation was assessed according to the method by Tanner and the sizes of their testes were measured using an ultrasound machine. The research information was analysed and a statistical value less than 0.05 was taken to mean that there was a difference between the measured variables. The mid-testicular sizes of the SCA participants were noted to be higher than that of their controls during the prepubertal period while the non-SCA boys had higher sizes from puberty onwards. The frequency of testicular pain, weight and pubic hair stage of the SCA boys were important contributors to their increased testes sizes, irrespective of pubertal status. Efforts aimed at preventing painful crisis should start during early childhood to forestall future sexual challenges in adulthood.