Thyroid cancer is the most rapidly increasing cancer type among women and the second among men. Early detection greatly improves the prognosis. For this purpose, the platelet distribution width (PDW), an early indicator of platelet activation, might be useful. The aim of this study was to investigate the ability of PDW and serum albumin levels individually or in combination to distinguish between thyroid cancer and benign thyroid nodules. A total of 265 patients with thyroid cancer and 243 with benign thyroid nodules were included in a development set. Then, two groups of 130 cases were enrolled in a validation set. Patient characteristics and hematologic test data at initial diagnosis were collected. Receiver operating characteristic curves (ROC), area under the curve (AUC) values, sensitivity and specificity were estimated. Albumin levels are significantly lower and PDW significantly higher in patients with thyroid cancer compared to the benign cases. Moreover, PDW values prominently differed among three types of thyroid cancer. In addition, the combination of PDW and albumin exhibited a significantly larger AUC than either marker alone (p < 0.001). In conclusion, the combined use of PDW and albumin might be useful in distinguishing thyroid cancer from benign thyroid nodules. This promising approach could be helpful in early detection of thyroid cancer.