Background <p>This study aims to explore the impact of type 2 deiodinase (<i>DIO2</i>) polymorphisms on TSH suppression therapy and quality of life in patients with papillary thyroid cancer.</p> Methods <p>A cohort of 200 patients with papillary thyroid cancer was recruited at Zhongshan Hospital, Xiamen University, between September 2021 and September 2022, with 88 in the lobectomy group and 74 in the total thyroidectomy plus ¹³¹I treatment group. Clinical data were collected, and quality of life was evaluated using the EQ-5D-3L scale. Genetic polymorphisms rs225014 and rs12885300 of <i>DIO2</i> were analyzed from whole blood samples.</p> Results <p>In comparison between the two surgical treatments, the total thyroidectomy plus ¹³¹I treatment group had lower scores in usual activities (<i>P</i> = 0.016), anxiety/ depression (<i>P</i> &lt; 0.001), EQ-5D index (<i>P</i> &lt; 0.001), and EQ VAS (<i>P</i> &lt; 0.001) than the lobectomy group. In the lobectomy group, <i>DIO2</i> rs225014 and rs12885300 polymorphisms did not significantly impact quality of life, thyroid hormone levels, or replacement therapy doses. However, in the total thyroidectomy plus ¹³¹I treatment group, patients with <i>DIO2</i> rs225014 wild type (AA) exhibited higher EQ-5D index scores than those with mutant types (AG, GG) (<i>P</i> = 0.025). In a multiple linear regression model, using L-T4 Dose/Weight as the dependent variable, <i>DIO2</i> rs225014 mutant types (AG, GG) were positively correlated with L-T4 Dose/Weight (β = 0.244, <i>P</i> = 0.028).</p> Conclusion <p>Patients in the lobectomy group exhibited higher quality of life than those in the total thyroidectomy plus ¹³¹I treatment group. In the latter, <i>DIO2</i> rs225014 mutant genotypes (AG, GG) showed a modestly lower EQ-5D index score and a slight association with higher L-T4 dose/weight ratios. No significant differences were found for <i>DIO2</i> rs12885300. These findings, limited by sample size and effect size, require validation in larger, multicenter studies.</p>