Background: Serum creatinine (S<sub>cr</sub>) in early neonatal life (first week of life) displays extensive variability; hence, a better understanding is needed to use S<sub>cr</sub> as a diagnostic biomarker for acute kidney injury (AKI). Objective: The objective of this study was to explore S<sub>cr</sub> trends and its covariates in early neonatal life. Methods: Analysis of a rich, pooled S<sub>cr</sub> dataset (enzymatic assay) of 4,509 S<sub>cr</sub> observations in 1,181 neonates in the first week of life with birth weight, gestational age (GA), and postnatal age as covariates was conducted. Descriptive data were summarized as median and range. The Spearman rank correlation test was used to examine S<sub>cr</sub>, while the Mann-Whitney U test was used to determine the differences between the different GA (≤32, 33–36, or ≥37 weeks) categories. Results: The median S<sub>cr</sub> at delivery was 55.7 (range 28.3–194.5) µmol/L, correlating with birth weight (r = 0.088) or GA (r = 0.183) for the full dataset. At birth, the median S<sub>cr</sub> was highest in term (≥37-week) neonates. In early neonatal life (median S<sub>cr</sub> values), there was a gradual increase to attain a peak S<sub>cr</sub> by day 2–3, highest and most delayed in neonates ≤32 weeks GA. This is followed by a blunted decrease when ≤32-week neonates were compared to those of 33–36 or ≥37 weeks GA. Conclusions: The S<sub>cr</sub> pattern in early neonatal life is complex, with the highest S<sub>cr</sub> at birth in full-term neonates, while those ≤32 weeks GA displayed the highest and delayed peak S<sub>cr</sub> with a subsequent blunted decrease. Knowledge of these patterns is crucial to explore the utility of S<sub>cr</sub> as an AKI biomarker.