Background: This study aimed to assess the effectiveness of a combined approach involving psychological nursing and fluoxetine in improving the mental well-being and quality of life in patients undergoing hysterectomy. Methods: Patients were categorized into three groups: control, intervention group A, and intervention group B, based on the nursing plan. The control group received routine nursing care, whereas intervention group A received routine nursing care and psychological support. Intervention B received routine nursing care, psychological support, and fluoxetine treatment. Psychological symptoms, anxiety, depression, quality of life, and nursing satisfaction were compared between the three groups before and after nursing interventions. Results: The outcomes of intervention groups A and B were superior to those of the control group. Furthermore, intervention group B outperformed intervention group A. After the interventions, the nursing satisfaction was higher in both intervention groups, A and B, compared to the control group. In contrast, intervention B exhibited the highest satisfaction scores, surpassing those of intervention group A. Conclusions: The combination of psychological nursing and fluoxetine therapy for patients with endometrial cancer undergoing hysterectomy holds significant promise in alleviating anxiety and depression, improving their overall quality of life, and increasing nursing satisfaction.