C-reactive protein (CRP) is a well-established marker of inflammation in neonates. Recent studies have shown the potential of CRP velocity as an early indicator of infection disorders in children and adults. However, data on CRP dynamics in the neonatal population remain limited. Our objective was to assess the dynamics of CRP levels and determine their clinical relevance in newborns admitted to the nursery. This is a retrospective review of medical records of neonates ≥ 35 weeks of gestation with a birth weight of ≥ 2000 g, who underwent partial sepsis work-up with at least 2 consecutive CRP measurements within the first 48-h of life, between January and December 2020. CRP dynamics were analyzed using CRP velocity (CRPv, mg/L/h), calculated by dividing the interval between the first two consecutive CRP measurements by the corresponding interval time. A total of 212 neonates were included in the study. Neonates admitted to the neonatal intensive care unit (NICU) presented with higher levels of CRPv (p = 0.047), and were more likely to experience hypoglycemia (p = 0.023) and respiratory distress (p = 0.023). Lower CRPv levels were associated with elective cesarean surgery (p = 0.043). Among neonates with CRPv ≥ 2 mg/L/h, female infants exhibited even higher CRPv values (p = 0.018). Only two cases of blood culture-confirmed neonatal sepsis were identified, with CRPv values of 3.22 and 0.02 mg/L/h., Neither case required NICU admission. Regression analyses revealed that higher gestational age was significantly associated with elevated CRPv levels (p = 0.004) whereas hypothermia was linked to lower CRPv values (p = 0.031). In neonates, CRP dynamics generally corresponded to their overall clinical condition but were also influenced by various non-infectious factors, including GA, mode of delivery and gender. Additionally, neonatologists should consider the recent finding that neonatal hypothermia was associated with decreased CRP levels when assessing ill-appearing newborns with low CRP measurements.