Objective To evaluate the effectiveness of critical care ultrasound and noninvasive cardiac output monitoring (NICOM) in guiding fluid resuscitation in neonatal septic shock by dynamically assessing responsiveness to fluid therapy and comparing treatment outcomes and clinical applicability. Methods A total of 51 neonates were enrolled. Before initiation of fluid resuscitation, patients were randomly assigned to receive fluid resuscitation guided by critical care ultrasound or by NICOM. Differences in 14-day mortality and other clinical outcomes after the onset of septic shock were compared between the two groups. Results No significant difference was found in 14-day mortality between the critical care ultrasound group and the NICOM group (P>0.05). The cumulative duration of vasoactive drug use was shorter in the NICOM group than in the critical care ultrasound group (P<0.05). The incidences of acute kidney injury and intracranial hemorrhage within 72 hours in the NICOM group were lower than in the critical care ultrasound group (both P<0.05). However, the duration of invasive mechanical ventilation was shorter in the critical care ultrasound group than in the NICOM group (P<0.05), and the incidence of pulmonary edema within 72 hour was lower (P<0.05). No significant differences were observed between the two groups in length of hospital stay, time to achieve lactate <2 mmol/L, or the incidences of cardiac dysfunction and hepatic dysfunction (all P>0.05). Conclusions In neonates with septic shock, the risks of acute kidney injury and intracranial hemorrhage within 72 hours are lower under NICOM guidance than with critical care ultrasound, whereas fluid resuscitation guided by critical care ultrasound reduces the risk of pulmonary edema. Both critical care ultrasound and NICOM are simple, low-cost, noninvasive tools that can assist in guiding fluid resuscitation in neonatal septic shock.