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Demoralization syndrome is prevalence among cancer patients in China. However, little research has examined how demoralization syndrome is associated with quality of life (QOL). The aims of this study were to investigate the relationship between mindfulness state, demoralization syndrome and QOL of thyroid cancer patients, and explore the mediating effect of mindfulness on demoralization syndrome and QOL. A correlational cross-sectional study was performed using an online questionnaire. The study was conducted from July to October 2022 among 310 thyroid cancer patients. General information questionnaire, the Demoralization Scale, Five Facet Mindfulness Questionnaire, short form health survey questionnaire were used for investigation. Calculations were performed using SPSS Statistics, version 25. Descriptive statistics, correlation, and process plug-in mediation effect analyses were used to analyze the data. A total of 310 valid questionnaires were finally recovered. The Five Facet Mindfulness Questionnaire score of 310 patients was (120.80 ± 16.57), Demoralization Scale score was (12.49 ± 4.73), short form health survey questionnaire score was (146.15 ± 28.46). Mindfulness played a partial mediating role between demoralization syndrome and QOL of thyroid cancer patients, and the mediating effect accounted for 68.57% of the total effect. Demoralization syndrome can influence QOL through mindfulness state. Measures are needed to increase the QOL of thyroid cancer patients by developing mindfulness programs to decrease their demoralization syndrome.