Objective To explore the therapeutic effects of contrast-enhanced ultrasound (CEUS) and color Doppler flow image (CDFI) -guided percutaneous microwave ablation in the treatment of benign thyroid nodules. Methods A total of 125 patients with benign thyroid nodules admitted to Puyang Hospital of Traditional Chinese Medicine from May 2021 to May 2024 were included in the study. According to the random number table group, 62 patients in the control group received CDFI-guided percutaneous microwave ablation, and 63 patients in the observation group received CEUS-guided percutaneous microwave ablation. The ablation effect, levels of thyroid hormone [Free Thyroxine (FT4), Thyroid-Stimulating Hormone (TSH), Free Triiodothyronine (FT3)] and incidence of complications were observed in the two groups. Results The total ablation rate of observation group (95.24%) was higher than that of control group (83.87%), and the nodule volume was smaller at different time points after operation (P<0.05). There was no significant difference in FT4, TSH and FT3 levels after operation between the two groups (P>0.05). Compared with the control group (16.14%), the incidence of complicatios in the observation group (4.77%) was lower (P<0.05). Conclusion In the treatment of benign thyroid nodules, compared with CDFI-guided percutaneous microwave ablation, CEUS-guided percutaneous microwave ablation can improve the ablation effect, without affecting thyroid hormone levels, maintain the relative stability of the endocrine system, and help reduce the incidence of postoperative complications.