Anxiety, depression and psychological flexibility appear to be correlated with quality of life in cancer patients. However, the mediating role of psychological flexibility between emotional distress and quality of life are unclear. The aim of the study was to investigate the mediating role of psychological flexibility in the relationships between anxiety, depression, and quality of life in cancer patients undergoing treatment. A hundred and nineteen cancer patients participated in the study by completing the Hospital Anxiety and Depression Scale, the Action and Acceptance Questionnaire II, and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, version 3. Anxiety and depression correlated with psychological flexibility and quality of life. Psychological flexibility correlated with the quality of life scales but not with the diarrhoea and constipation. Mediation analysis showed that depression and anxiety indirectly influenced cognitive and social function through psychological flexibility. Depression indirectly influenced emotional functioning, dyspnoea and insomnia. The results obtained suggest that psychological flexibility may affect the relationship between emotional distress and different aspects of quality of life for cancer patients.Trial registration This research has been registered in www.ClinicalTrials.gov , identifier [NCT05126823] in 19/11/2021.