Introduction Platelets (PLTs) are dynamic blood molecules which perform multiple physiological functions. Platelet derangements are commonly encountered in intensive care units (ICUs). The relationship of PLT indices with all-cause mortality, acute physiology and chronic health evaluation IV (APACHE IV), diabetes mellitus (DM), and length of stay in ICU is debatable and hence this study was undertaken to bridge this gap of knowledge. Materials and methods Prospective data were collected for 20 months in the ICU of our hospital. Platelet indices were analyzed among survivors and non-survivors. Acute physiology and chronic health evaluation IV scores were used to study the relationship between PLT indices and illness severity. Receiver operating characteristic curves were constructed to compare the performances of PLT indices in predicting mortality, while the effect of DM on PLT indices was evaluated using regression analysis. Results A total of 170 out of 345 patients (119 survivors, 51 non-survivors) met the study criteria. Patients with decreased PLT count and plateletcrit (PCT) ( p < 0.001 and 0.001, respectively), increased mean platelet volume (MPV) and platelet distribution width (PDW) ( p = 0.014 and 0.004, respectively) had a significant correlation with increased risk of mortality than those with normal PLT indices. These patients also had a higher APACHE IV and acute physiology score ( p < 0.001). No significant relationship was found between the PLT indices and the length of ICU stay. The influence of each PLT index adjusted to DM was significant in univariate regression analysis, whereas in multivariate only PDW had a significant influence. Conclusion Patients with low PLT, PCT and high MPV, PDW were associated with more severe illness, poor prognosis, and a higher risk of mortality. Platelet distribution width is the preferred PLT index in a diabetic patient to predict clinical status. Clinical significance Platelet indices which are routinely available can be effectively used as a morbidity and mortality indicator in critically ill patients. How to cite this article Samuel D, Bhat AN, Prabhu VM. Platelet Indices as Predictive Markers of Prognosis in Critically Ill Patients: A Prospective Study. Indian J Crit Care Med 2020;24(9):817–822.