Objective: We report three cases of preterm neonates who presented with central nervous system (CNS) and respiratory depression after inadvertent exposure to brimonidine tartrate 0.2% and timolol maleate 0.5% fixed-combination ophthalmic drops. Case descriptions: CNS and respiratory depression were observed in the three neonates within two hours of administration of brimonidine tartrate 0.2% and timolol maleate 0.5% eye drops. Respiratory support was initiated upon admission to the neonatal intensive care unit (NICU). The effects of the drug combination lasted for 24 to 48 hours. Conclusion: This case series suggests that the drug combination of brimonidine tartrate and timolol maleate causes a prolonged depression of the central nervous and respiratory systems in preterm neonates.