Purpose <p>This study aims to define the relationship between the serum thyroglobulin change rate (ΔTg) after radioactive iodine (RAI) therapy and both RAI therapy response as well as prognosis in pediatric patients with differentiated thyroid cancer (DTC) presenting with postoperative persistent structural disease.</p> Methods <p>This retrospective study analyzed 123 RAI courses in 57 pediatric DTC patients with postoperative persistent structural disease. Treatment response was assessed at 6 months post-RAI. Optimal ΔTg thresholds for response classification were determined using ROC analysis with bootstrap validation. The prognostic value of ΔTg for achieving no evidence of disease (NED) and progression-free survival (PFS) was evaluated.</p> Results <p>ΔTg values differed significantly among response categories (<i>p</i> &lt; 0.001). Median ΔTg values were as follows: Complete Response (CR), 84.5%; Partial Response (PR), 53.8%; Stable Disease (SD), 4.9%; Progressive Disease (PD), -69.0%. ROC analysis identified optimal ΔTg thresholds: ΔTg ≥ 32% for predicting achievement of Objective Response (OR; CR + PR), and ΔTg ≤-14% for predicting PD occurrence. Patients with ΔTg values between − 14% and 32% were classified as having SD. Longitudinally, initial ΔTg ≥ 32% vs. initial ΔTg ≤-14% showed superior PFS (<i>p</i> &lt; 0.001) and higher NED rates. The intermediate group (-14%&lt;ΔTg &lt; 32%) exhibited outcome dissociation: NED rate aligned with ΔTg ≤-14%, while PFS resembled ΔTg ≥ 32%. Multivariable analysis confirmed ΔTg ≤-14% predicted an 11.7-fold higher progression hazard (HR = 11.70, 95%CI:3.27–41.89; <i>p</i> &lt; 0.001).</p> Conclusions <p>This study establishes validated ΔTg thresholds for response assessment in pediatric DTC with persistent structural disease (OR: ≥32%; PD: ≤-14%; SD: -14%&lt;ΔTg&lt;32%). Initial ΔTg is a powerful independent prognostic factor. These evidence-based thresholds provide actionable guidance for managing pediatric DTC patients with postoperative persistent disease.</p>