Background: The discriminative utility of the neonatal sequential organ failure assessment (nSOFA) for early-onset sepsis (EOS) mortality in the neonatal intensive care unit (NICU) is unknown. Objectives: The objective of the study was to determine the utility of nSOFA for EOS mortality. Methods: Multicenter, retrospective cohort study of NICU patients with EOS between 2012 and 2023. nSOFA scores of survivors and non-survivors were compared, and area under the receiver operating characteristics curve (AUROC) for mortality was calculated. Results: 104 subjects were identified (88 lived, 16 died). AUROC at blood culture collection (T0), 6 h after collection (T6), and the maximum nSOFA at T0 or T6 (T0–6max) were 0.76 (95% CI: 0.62, 0.91), 0.89 (0.80, 0.99), and 0.87 (0.77, 0.97), respectively. Analyses restricted to birthweight (<1.5, <1 kg) or gestational age (<32, <29 week) cutoffs revealed AUROC ranges of 0.86–0.92 for T6 and 0.82–0.84 for T0–6max. Conclusions: The nSOFA showed good-to-excellent discrimination of mortality among infants with EOS in the NICU.