BACKGROUND: Sickle cell anaemia (SCA) is highly prevalent in sub-Saharan Africa and is characterized by frequent vaso-occlusive crises and other severe complications. Hydroxyurea has proven effective in reducing SCA complications by increasing foetal haemoglobin, but its use in low- and middle-income countries (LMICs) remains limited due to cost, need for regular laboratory monitoring, and concerns about safety. This study evaluates a simplified hydroxyurea dosing regimen as a practical approach to reduce emergency room visits and improve treatment adherence in paediatric SCA within a resource-limited setting. METHODS: We conducted a prospective open-label cohort study over two years (January 2022– January 2024) at a tertiary hospital in South East Nigeria. One hundred children aged 1–18 years with confirmed SCA (HbSS genotype) were started on a uniform dose of hydroxyurea (20 mg/kg/day, capped at 500 mg/day). Patients were followed monthly, and those experiencing “breakthrough vaso-occlusive crises” had their dose increased to 25 mg/kg/day (or from 500 mg to 750 mg for those at the capped dose). The primary outcome was the frequency of SCA-related emergency room visits. Secondary outcomes included treatment adherence (assessed via caregiver report of missed doses) and factors associated with adherence. Statistical analyses (t-tests, Mann–Whitney U, chi-square) were performed to compare clinical and demographic variables between adherence groups, with a significance threshold of  < 0.05. RESULTS: The simplified hydroxyurea regimen dramatically reduced emergency room visits. Only one patient (1% of the cohort) required an emergency visit for a vaso-occlusive crisis during the two-year period, and this patient’s dose was successfully escalated to 750 mg/day with no further crises. Overall, treatment adherence was high: 84.2% reported consistent adherence to daily hydroxyurea. Younger children demonstrated better adherence than older children (mean age of adherent patients 8.5 ± 5.3 years vs. 11.6 ± 4.2 years for non-adherent,  = 0.027). Patients who were non-adherent tended to have older fathers (median paternal age 49 years vs. 44 years in adherent patients,  = 0.02). Other factors—sex, socio-economic status (social class), maternal age, weight, and baseline health status—showed no significant association with adherence (all  > 0.2). No severe adverse effects were observed, and the dosing approach was well-tolerated without routine laboratory monitoring. CONCLUSION: A simplified hydroxyurea dosing strategy appears to be a safe, effective, and feasible strategy for managing paediatric SCA in a resource-limited setting. This approach resulted in a substantial reduction in vaso-occlusive crises requiring emergency care and high levels of treatment adherence. These findings suggest that simplified dosing protocols could be a valuable component of broader SCA care strategies in settings such as Nigeria. Validation through larger or comparative studies is encouraged, and we recommend that healthcare policy-makers consider piloting and supporting similar models as part of national sickle cell control efforts. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12887-025-05834-y.