Background: The appropriate identification of target patients for methylxanthine therapy may optimize resource allocation and improve clinical outcomes, but data on routine care in low-resource settings are limited. Our study assessed methylxanthine use in clinical practice in two Sub-Saharan settings. Methods: This retrospective, registry-based study investigated methylxanthine use in newborns who were admitted to Tosamaganga Hospital (Tanzania) and Wolisso Hospital (Ethiopia) in 2022-2023. The prevalence and type of methylxanthine treatment were investigated. Neonates receiving methylxanthine were compared to those not receiving it in terms of baseline characteristics, clinical data, treatments, and discharge information. All data were retrieved from local registries. Results: Aminophylline was administered to 196/1674 neonates (11.7%), while caffeine was not available in these settings. This treatment was more common in preterm and smaller infants (p < 0.0001), asphyxiated neonates (p < 0.0001), and the sickest patients (p < 0.001). The need for respiratory support (p < 0.0001), intravenous lines (p < 0.0001), and antibiotic therapy (p < 0.0001), as well as the length of hospital stay (p < 0.0001) and mortality rate (p < 0.0001), were higher in neonates receiving aminophylline. Conclusions: In two Sub-Saharan settings, methylxanthine treatment was limited to aminophylline, which was given to around 12% of infants admitted to the special care units. Overall, the treatment was appropriately given to most eligible neonates, although a considerable subgroup of very preterm infants did not receive aminophylline prophylaxis. Further studies may investigate the reasons for protocol incompliance regarding aminophylline treatment and healthcare staff's opinions on such an aspect.