Patent ductus arteriosus (PDA) is the most common cardiac condition in preterm infants. The most commonly used drugs for this purpose are cyclooxygenase inhibitors, mainly indomethacin and ibuprofen, which block the conversion of arachidonic acid to prostaglandins. On the other hand, several adverse effects have been reported with such medications, including peripheral vasoconstriction, gastrointestinal bleeding and perforation, weakened platelet aggregation, hyperbilirubinemia and renal failure. The role of oral paracetamol as an alternative treatment for the closure of PDA has gained importance in recent years. In this review, we aimed to determine safety of therapeutic drugs used in management of PDA in preterm infants rather than their efficacy in ductal closure. Two worldwide commonly used therapeutics (indomethacin and ibuprofen) and a new alternative medication as paracetamol are discussed. Ibuprofen seems to be the first choice due to its higher safety profile, as it is associated with fewer gastrointestinal and renal side effects than indomethacin. Recent studies suggest that paracetamol may be a medical alternative in the management of PDA with low adverse events and side effects.