Background Early administration of intravenous (IV) caffeine (initiation within 2 days of life) is an effective treatment strategy for the management of apnoea of prematurity among infants. However, the safety and effectiveness of early administration of oral caffeine treatment is not be fully established. Aim We aimed to compare the effectiveness and safety of early versus late caffeine therapy on preterm infants’ clinical outcomes. Method A retrospective matched cohort study was conducted using data of patients admitted to neonatal intensive care units of two tertiary care hospitals between January 2016 and December 2018. The clinical outcomes and mortality risk between early caffeine (initiation within 2 days of life) and late caffeine (initiation ≥ 3 days of life) were compared. Results Ninety-five pairs matched based on gestational age were included in the study. Compared to late initiation, preterm infants with early caffeine therapy had: a shorter duration of non-invasive mechanical ventilation (median 5 days vs. 12 days; p < 0.001); shorter length of hospital stay (median 26 days vs. 44 days; p  < 0.001); shorter duration to achieve full enteral feeding (median 5 days vs. 11 days; p < 0.001); and lower frequency of bronchopulmonary dysplasia (BPD) (4.5% vs. 12.9%; p = 0.045). They also had a reduced risk of osteopenia of prematurity (OP) (OR 0.209; 95% CI 0.085–0.509; p = 0.001). Conclusion Early oral caffeine therapy can potentially improve respiratory outcomes among infants with apnoea of prematurity. However, an increase in mortality associated with early caffeine therapy requires further investigation.