Background <p>This study aimed to compare the efficacy and safety of ultrasound-guided intermediate cervical plexus block (ICPB) versus local infiltration anesthesia (LIA) for thermal ablation of benign thyroid nodules (BTNs). Given the high prevalence of pain during thermal ablation, we hypothesized that ICPB would provide non-inferior analgesia compared to LIA while enhancing postoperative outcomes.</p> Methods <p>We conducted a double-blind, non-inferiority randomized controlled trial involving 105 patients with BTNs. Participants were randomly assigned to receive either ICPB combined with low-dose LIA or LIA alone. The primary outcome was the proportion of patients achieving a Numeric Rating Scale (NRS) score of less than 4 during the procedure. Secondary outcomes included postoperative pain scores, adverse effects, and patient satisfaction.</p> Results <p>In the ICPB group, 63.5% of patients achieved an NRS score of less than 4 compared to 64.2% in the LIA group, with no significant difference (<i>p</i> = 0.941). However, the ICPB group reported significantly lower incidences of postoperative pain (NRS &gt; 0) and neck swelling compared to the LIA group (<i>p</i> = 0.037 and <i>p</i> = 0.024, respectively). Adverse effects such as paraesthesia pharynges were also significantly lower in the ICPB group (7.7% vs. 24.5%, <i>p</i> = 0.019).</p> Conclusions <p>Ultrasound-guided (USG) ICPB combined with low-dose LIA offers comparable intraoperative analgesia to LIA alone while improving postoperative pain management and reducing adverse effects in patients undergoing thermal ablation for BTNs. The trial provides moderate evidence supporting non-inferiority for intraoperative analgesia with superiority signals in selected 24-hour outcomes. This technique may represent a valuable alternative for enhancing patient comfort during such procedures.</p> Trial registration <p>Full name of the registry: Chinese Clinical Trial Registry. Trial registration number: ChiCTR2100044094. Date of registration:2021/03/11.</p>