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Background/Objectives: Structural incomplete response (SIR) (persistence/recurrence) may occur in 2–6% of low-risk differentiated thyroid cancer (DTC)-cases and in 67–75% of high risk. Regarding locoregional disease, surgery is the optimal therapeutic modality if the smallest dimension of the targeted node is ≥8 mm or ≥10 mm (central or lateral compartment). In the presence of smaller nodes, contraindications or the patient’s unwillingness for reoperation, active surveillance (AS) or minimally invasive treatments (MITs) may be considered. Methods: We retrospectively studied eight DTC patients with SIR confirmed by ultrasound (U/S)-guided fine-needle aspiration cytology (FNAC) and the measurement of Thyroglobulin (Tg) in the washout fluid. Fourteen malignant lesions were ablated by radiofrequency (RF). We assessed prior to RF ablation (RFA) and consecutively at one month, three months and, then, every three months the volume of each lesion, serum Tg and Anti-Tg antibodies and calculated the volume reduction ratio (VRR). Results: Patients were followed for a mean period of 13.25 months (range: 4–24) after RFA was performed. The targeted lesions reduced significantly from a median volume of 0.24 mL (range: 0.09–0.9) to 0.02 mL (range: 0–0.03) (p < 0.05), with a median VRR of 94.5% (range: 78–100%) and concomitant significant biochemical remission (decrease in serum Tg from a median of 1.05 ng/mL to 0.2 ng/mL, p < 0.05). In one patient with an aggressive radioiodine (RAI)-refractory histological variant, re-recurrence was documented, which was successfully re-ablated by RF. In two patients, Horner syndrome was diagnosed as an RFA complication, which was totally resolved within six months. Conclusions: RFA may be considered as an effective and safe MIT in selective DTC patients with SIR, especially in cases of smaller lesions. Additional prospective studies are needed, including aggressive DTC histological variants towards a tailored therapeutic approach.