Pre-procedural antisepsis is a critical component of hospital-acquired infection prevention in the neonatal intensive care unit (NICU). However, broadly utilized topical antiseptic agents pose an elevated risk of disruption to neonatal skin integrity, and evidence-based guidelines are lacking. This systematic review of the literature sought to assess and characterize the predisposing risk factors for and types of neonatal skin injury from topical antiseptic agents. A systematic search of Medline Ovid, Embase, Web of Science, CINAHL, and Cochrane Library was conducted, including academic literature providing data on neonatal skin injuries related to topical antisepsis in the NICU. A total of 19 articles (99 patients) met the inclusion criteria. Of the available data, most reported skin injuries were described in extremely preterm (98.1%) and very low birth weight (98.4%) infants. The majority of reported adverse cutaneous events were attributed to chlorhexidine preparations (74.8%), followed by octenidine (18.2%), povidone-iodine (6.1%), and isopropyl alcohol (2.0%). Erythema (40.1%), skin breakdown (23.4%), and chemical burns (17.5%) were the skin reactions reported most frequently, followed by skin irritation (8.3%), and skin necrosis (2.8%). Our findings indicate that both extremely preterm and very low birth weight infants are particularly susceptible to skin toxicities from pre-procedural antiseptic preparations. These data underscore the need for future research to support the development of guidelines which minimize iatrogenic cutaneous injuries in the neonatal population, specifically for the care of infants under 2 months of age, for whom current recommendations are lacking due to a paucity of data.