Background Thrombocytopenia (platelet count below 150 x 103/μL) is a common finding after open-heart surgery and can lead to various complications, including patient death. This study aimed to determine the extent of non–heparin-induced thrombocytopenia in open-heart surgery and to highlight the associated factors. Materials and Methods In this cohort study, 842 patients who underwent valve and/or coronary bypass surgery over a 5-year period were retrospectively analyzed. After open-heart surgery, patients whose platelet count was less than 150 x 103/μL on a complete blood count 12 and 24 h after surgery were classified as thrombocytopenic. Three hundred twenty patients without thrombocytopenia and 21 patients with a high probability of heparin-induced thrombocytopenia were excluded from the study. Logistic regression analysis was used to assess the association of independent variables in moderate-severe thrombocytopenia: Age groups, sex, underlying disease, symptoms, type of surgery, pump time, pulsatile or non-pulsatile duration, degree of hypothermia, hemodilution, oxygenator type, use of an intra-aortic balloon, and erythrocyte transfusion counts were included in the analysis. Results A total of 501 patients were diagnosed as having non–heparin-induced thrombocytopenia, and 64.3% were male. Three hundred seventy-seven (75.2%) patients had mild thrombocytopenia and 124 (24.7%) had moderate-severe thrombocytopenia. The postoperative platelet count was significantly lower than the preoperative platelet count (213 x 103 vs.117 x 103/μL; p < 0.001). Moderate-severe thrombocytopenia was associated with age ≥80 years odds (OR = 9.026, 95% CI: [1.757–46.363]; p = 0.008), isolated valve surgery (OR = 3.090, 95% CI: [1.867–5.114]; p < 0.001), and valve surgery with coronary bypass (OR = 4.938, 95% CI: [1.638–14.889]; p = 0.005) compared to isolated coronary bypass, type of oxygenator (Nipro vital compared with Affinity OR = 11.097, 95% CI: [1.923–64.023]; p = 0.007), erythrocyte transfusion count (OR = 1.219, 95%CI: [1.046–1.420]; p = 0.011). Conclusion Age 80 years or older, surgical procedures including heart-valve surgery, and the number of red blood cell transfusions are associated with the risk of moderate-to-severe thrombocytopenia. This study provides a guide in terms of risk factors that may lead to moderate-to-severe thrombocytopenia after open-heart surgery. However, future multicentre prospective randomized studies may provide more detailed information on this subject.