Abstract: Objective To explore the effect of dexmedetomidine combined with esketamine on postoperative anxiety and neuropsychiatric symptoms in patients undergoing radical mastectomy for breast cancer. Methods A total of 130 patients who were scheduled for elective radical mastectomy under combined intravenous-inhalation anesthesia were randomly divided into three groups: control (group C), esketamine (group ES), and esketamine combined with dexmedetomidine (group ES+DE). In addition to baseline anesthetics which were the same in all groups, each group was continuously infused with the corresponding anesthetics, and pain management was performed with additional administration of the corresponding drugs in groups ES and ES+DE. Changes in heart rate (HR) and mean arterial pressure (MAP) were compared between groups during surgery. Postoperative adverse reactions and neuropsychiatric symptoms was recorded. Pain and anxiety scores were assessed. Results There were no statistical differences in general information among the three groups. Compared with groups C and ES, HR in group ES+DE significantly decreased at extubation (T2) (P<0.01 or P<0.05). Compared with group C, MAP in group ES+DE significantly decreased at T2 (P<0.01). There were no statistical differences in pain scores at postoperative 6, 24, and 48 h among the three groups (P>0.05). Compared with groups C and ES, group ES+DE showed significantly reduced incidences of adverse reactions and neuropsychiatric symptoms (P<0.01). Further results indicated that, compared with groups C and ES, group ES+DE presented significantly reduced anxiety symptoms at postoperative 24 and 72 h (P<0.01 or P<0.05). Conclusions The combination of dexmedetomidine and esketamine significantly alleviates postoperative anxiety and neuropsychiatric symptoms in breast cancer patients undergoing radical mastectomy.