Neonatal sepsis (NS) continues to be a diagnostic challenge and a prime cause of mortality. Forage for a lucid, cost-effective yet highly sensitive and specific marker in diagnosing this entity is an incessant task. This study aimed to evaluate the predictive value of mean platelet volume (MPV) in diagnosing NS. Neonates diagnosed with sepsis from January 2016 to March 2016 were included in the study. The subjects were stratified into the following: (i) culture-proven sepsis (group I); (ii) culture-negative clinical sepsis (group II); and (iii) control group (group III). Several hematologic markers such as hemoglobin, total leukocyte count, platelet count, MPV, plateletcrit, platelet distribution width, immature-to-mature neutrophil ratio, toxic change, serum urea, bilirubin, and C-reactive protein were analyzed. The results were compared among the groups, and their efficacy in diagnosing NS was appraised. The study involved 210 neonates, of which, groups I, II, and III constituted 64, 75, and 71 cases, respectively. The mean MPV among groups I, II, and III was 9.56, 8.86, and 8.58 fL, respectively (P<0.05). Strikingly higher values of platelet count, immature-to-mature neutrophil ratio, MPV, plateletcrit, and C-reactive protein were found in group I in contrast to those in groups II and III (P<0.05). The baseline MPV of patients with culture-proven sepsis was comparatively higher than controls and was found to be statistically significant. Hence, MPV can be a simple, economical, and specific predictor of NS.