Objective To investigate the effect of low-dose dexmedetomidine on sedation and rehabilitation in elderly patients with breast cancer after radical mastectomy. Methods From February 2018 to July 2020, 137 elderly patients with breast cancer in our hospital were prospectively collected and randomly divided into observation group (n=69) and control group (n=68). All patients underwent radical mastectomy and received general anesthesia during the operation. The observation group was given low dose dexmedetomidine, and the operation, post-operative rehabilitation, stress response, sedation and cognitive function were observed between the two groups. Results There was no significant difference in operation time, number of lymph node dissection and amount of bleeding between the two groups (P＞0.05). When compared with the control group, the anal exhaust time (h) of the observation group was shortened (40.38±9.84 vs. 45.04±9.77 h,P=0.006); the drainage time was shortened (65.48±12.65 vs. 70.66±13.02 h, P=0.019); and the discharge time was shortened (9.84±2.47 vs. 10.74±2.44 d, P=0.034). There was no significant difference in preoperative corticotropin and C-reactive protein between the two groups (P＞0.05). When compared with the control group at 24 hours after operation, the corticotropin in the observation group decreased (4.24±1.71 vs.4.90±1.28 ng/mL, P=0.012); and C-reactive protein decreased (12.62±2.71 vs. 17.52±2.62 mg/L, P=0.000). There was no significant difference in BIS at T1 between the two groups (P＞0.05). When compared with the control group, the BIS of patients in the observation group decreased significantly at T2-T5 (P＜0.05). There was no significant difference in preoperative Mini-Mental State Examination (MMSE) score between the two groups (P=0.388). When compared with the control group at 24 hours after operation, the MMSE score in the observation group was significantly higher (24.92±1.98 vs. 23.71±1.83, P=0.000). Conclusion Low dose dexmedetomidine can reduce stress response, improve cognitive function and accelerate rehabilitation in elderly patients undergoing radical mastectomy.