Objective To study the effects of multimodal ultrasound-guided radiofrequency ablation on stress response and thyroid hormone levels in patients with benign thyroid nodules. Methods A total of 62 patients with benign thyroid nodules in Zhengzhou Traditional Chinese Medicine Hospital from January 2020 to June 2024 were selected and randomly assigned into two groups: the traditional group and the study group. 31 patients in the traditional group received traditional subtotal thyroidectomy, and 31 patients in the study group received multimodal ultrasoundguided radiofrequency ablation. The levels of thyroid hormone, stress response indexes, quality of life 3 months after operation and incidence of complications were compared between the two groups. Results After operation, serum levels of interleukin-8 (IL-8), hypersensitive C-reactive protein (hs-CRP) and tumor necrosis factor-α (TNF-α) were (21.44±2.28) ng/L, (3.65±0.86) mg/L and (26.57±2.22) ng/L respectively, all lower than those in traditional group, which were (24.38±2.27) ng/L, (6.74±1.20) mg/L, (29.45±3.52) ng/L (P<0.05). After operation, the serum TSH level in the study group was (2.39±0.57) mIU/L, which was lower than that of (3.05±0.57) mIU/L in the traditional group. The levels of free thyroxine (FT4) and free triiodothyronine (FT3) were (17.02±1.19) mmol/L and (5.34±1.15) mmol/L, respectively, which were higher than those of traditional group of (15.45 ±1.13) mmol/L and (4.78 ±0.87) mmol/L (P<0.05). The SF-36 score of the study group was 76.10±4.55, which was higher than that of the traditional group of 70.35±4.74 (P<0.05). There was no statistically significant difference in incidence of complications between the two groups (P>0.05). Conclusion Multimodal ultrasound-guided radiofrequency ablation can reduce the stress response of patients with benign thyroid nodules, protect thyroid function, improve quality of life, and demonstrates a high safety.