Despite dramatic declines in the incidence of ophthalmia neonatorum with universal prophylaxis, it remains a clinically important cause of eye disease in newborns. While clear guidelines exist for the treatment of the historically primary agents of ophthalmia neonatorum (Chlamydia trachomatis and Neisseria gonorrhoeae), it is less clear how to manage newborns with conjunctivitis secondary to other bacterial organisms, particularly those also frequently implicated in neonatal sepsis. We present the case of a 3-day-old well-appearing term infant with unilateral purulent conjunctivitis. The eye culture grew Escherichia coli, an unusual cause of ophthalmia neonatorum. After a limited sepsis evaluation proved negative, the infant was switched to moxifloxacin ophthalmic drops and made a full recovery. This case highlights the challenge of managing a rare presentation with minimal guideline support, as well as the need to consider other bacterial causes of neonatal conjunctivitis which are emerging in the era of routine prophylaxis in the United States.