Objective: Despite the expectation of normal life expectancy for thyroid cancer, there are concerns about the decreased quality of life (QoL). The present study investigated the potential risk factors of deterioration in QoL scores in thyroid cancer patients after thyroidectomy. Materials and methods: A total of 286 patients who were diagnosed with thyroid cancer after thyroidectomy were involved in this prospective, single-center, observational study from November 2018 to June 2019. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 was used to assess the QoL 3 months after thyroidectomy. We investigated the effects of demographics (age, gender, education, marital status, area of residence, and annual mean income), tumor characteristics (histology, clinical stage, presence of metastasis, surgery type, and radiotherapy), and neurological deficits induced by recurrent nerve or superior laryngeal injury on QoL. Results: The mean overall QoL in thyroid cancer survivors was 65.93 ±9.00 (on a scale of 0-100, where 100 was the best). Multivariate regression analysis confirmed that clinical stage (P < 0.010), surgery type (P < 0.001), histology (P < 0.001), neurological deficits (P < 0.001), and marital status (P < 0.001) were independent risk factors for decreased QoL 3 months after thyroidectomy. Conclusion: Our study indicated that clinical stage, surgery type, histology, neurological deficits, and marital status were independent risk factors for decreased QoL at 3 months after thyroidectomy. Further exploration and validation of these findings in larger prospective studies are warranted.