The present study was aimed to compare the application values between 2-dimensional color Doppler ultrasonography (2DUS) and contrast-enhanced ultrasonography (CEUS) in the differential diagnosis of thyroid malignant nodules.A total of 124 patients suspectedly diagnosed with malignant thyroid nodules under conventional gray-scale ultrasonography were recruited in this study. All enrolled patients were examined by both 2DUS and CEUS.A total of 153 nodules (94.44%) and 45 cases (90.00%) with malignant nodules were detected by the CEUS. No significant differences were noted in nodule detection rates between 2DUS and CEUS (χ = 1.170, P = .279; χ = 0.796, P = .372). The aspect ratio, microcalcification, internal echo, borderline, Vmax, resistance index, and total scores of malignant nodules were higher than those of benign nodules (all P < .05) when diagnosed by 2DUS. The peripheral/internal enhancement time, peak intensity, local enhancement, ring enhancement, and total scores of malignant nodules were significantly higher compared with those of benign nodules (all P < .05) by CEUS. Total score of malignant nodules diagnosed by 2DUS was approximately 3.5 and 2.3 points for CEUS. The diagnostic accuracy of 2DUS as observed by area under the curve was 0.821 with the cut-off value of 3.9, the sensitivity was 82.5%, and the specificity was 85.6%. The diagnostic accuracy of CEUS was 0.862 with the cut-off value of 2.8, the sensitivity was 86.7%, and the specificity was 91.3%.Both 2DUS and CEUS are worthy of application values in the differential diagnosis from benign to malignant thyroid nodules.