Extracorporeal perfusion systems utilized in open-heart surgeries with cardiopulmonary bypass can affect multiple body systems. The primary adverse effects of Extracorporeal Perfusion Systems (EPS) on the hematological system include postoperative bleeding and coagulation issues. The aim of this study is to evaluate the effects of on-pump time and cross-clamp duration on total platelet count (PLT) and platelet indices in open-heart surgeries performed using cardiopulmonary bypass. This evaluation is achieved by comparing PLT, mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT) before and after surgery. For this study, the laboratory results of a total of 392 patients who underwent open-heart surgery with cardiopulmonary bypass at the Department of Cardiovascular Surgery, Istanbul University Cerrahpaşa Institute of Cardiology, between 2017 and 2018 were retrospectively analyzed. The stepwise multiple linear regression model, in which postoperative PLT was the dependent variable and other parameters were independent variables, revealed that the main determinants of the significant change in postoperative PLT were the duration of device use, along with preoperative PLT and PDW. Our results indicate that on-pump time, along with preoperative PLT and PDW values, is the primary determinants of changes in PLT and PCT in open-heart surgeries with cardiopulmonary bypass. Considering the patient’s preoperative platelet count and PDW values in such surgeries may be useful in preventing postoperative adverse events.