Background: Neonatal sepsis is a leading cause of neonatal hospitalization, contributing to 26% of global neonatal deaths. Early diagnosis and treatment can improve the outcome of neonatal sepsis. This study aimed to evaluate MPV and PDW as markers for neonatal sepsis and their correlation with CRP levels. Materials and Methods: This cross-sectional study was conducted in the neonatal intensive care unit (NICU) between 1st January 2021 and July 2022. The study included 80 neonates with clinical signs of sepsis, positive sepsis screening, or infection risk factors as the case group, and 80 age- and gender-matched healthy neonates as the control group. At the time of clinical diagnosis and prior to antibiotic initiation, complete blood count (CBC) including platelet parameters—mean platelet volume (MPV), platelet distribution width (PDW), CRP were done. Results: The mean birth weight of neonates with sepsis was 2.5±0.7 days and in healthy neonates was 2.8±0.5 days, with a male:female ratio of 1:1 in both groups. Neonatal sepsis was found to be associated with several risk factors, including meconium aspiration, PROM, parity, prematurity, and low birth weight. MPV was notably elevated in affected neonates, which also demonstrated significant correlation with CRP levels. Conclusion: MPV could serve as useful diagnostic tools for neonatal sepsis.