Objective. This study was to evaluate the clinical efficacy of levothyroxine sodium tablets combined with I 131 in the treatment of patients after thyroidectomy and the effect on thyroglobulin (Tg) and thyroid stimulating hormone (TSH) levels. Methods. 80 patients with differentiated thyroid cancer who required thyroidectomy after surgery between July 2019 and January 2021 were recruited for prospective study, 40 patients in the control group received levothyroxine sodium tablets, and 40 patients in the experimental group received levothyroxine sodium treatment plus I 131 treatment. Treatment effect, serum Tg and TSH levels, and relapse were measured. Results. The removal rate of residual thyroid tissue in the experimental group (87.50%) was significantly higher than that in the control group (57.50%) ( P < 0.05 ). Levothyroxine sodium tablets plus I 131 was associated with a significantly higher efficacy versus levothyroxine sodium tablets ( P < 0.05 ). There were no significant differences in the serum Tg levels between the two groups before treatment ( P > 0.05 ). After treatment, the serum Tg levels in both groups were significantly decreased, and levothyroxine sodium tablets plus I 131 resulted in a significantly lower Tg level versus levothyroxine sodium tablets ( P < 0.05 ). Before treatment, the two groups showed similar TSH levels ( P > 0.05 ). After treatment, patients receiving levothyroxine sodium tablets plus I 131 had a significantly greater increase in the TSH levels versus levothyroxine sodium tablets ( P < 0.05 ). The recurrence rate of the experimental group was lower than that of the control group ( P < 0.05 ). Conclusion. Levothyroxine sodium tablets plus I 131 for post-operative patients with differentiated thyroid cancer enhance the removal rate of residual thyroid tissue, effectively reduce serum Tg level, and increase TSH level, with significant therapeutic effects, low recurrence rates, and a high safety profile.