This study aimed to examine whether anxiety and depressive symptoms mediate the relationship between performance status and health-related quality of life (HRQL) in patients with female cancer. A poor performance status is known to adversely affect HRQL and psychological distress-particularly anxiety and depressive symptoms-which may play a key role in this relationship. Identifying the mediating role of these symptoms may offer valuable insights into the mechanisms linking the performance status and HRQL. : In a cross-sectional, correlational study, data on the HRQL (EORTC QLQ Version 3), performance status (Eastern Cooperative Oncology Group), and anxiety and depressive symptoms (Hospital Anxiety Depression Scale) were collected between February 2019 and June 2021. Process v4.1 for SPSS was used to analyze the data. : Sixty-five patients with female cancer participated (breast cancer = 44; gynecologic cancer = 21; mean age = 55.03 ± 8.65 years). Anxiety ( = 0.002), but not depressive symptoms ( = 0.525), mediated the relationship between the performance status and HRQL, explaining 41% of the variance in the HRQL ( = 0.41, = 14.06, < 0.001). A better performance status was only indirectly associated with a better HROL through the effect on anxiety. The total effect of the performance status on the HRQL was 15.972 (confidence interval [CI] = 6.095, 25.849): direct effect = 7.226 (CI = -1.936, 16.389) and indirect effect = 6.878 (standardized indirect effect = 0.374) (CI = 1.195, 15.395). : The findings of this study only supported the mediating role of anxiety in the relationship between the performance status and HRQL in patients with female cancer. To improve the HRQL in patients with female cancer, improvements in the performance status and reductions in anxiety are critical.