Objectives <p>This study investigated the effects of different dexmedetomidine (DEX) doses on the occurrence of postoperative delirium (POD), assessed the levels of serum stress and inflammatory factors, and nerve injury markers in elderly patients undergoing radical mastectomy for breast cancer.</p> Methods <p>In this parallel randomized controlled study, 120 elderly patients undergoing radical mastectomy for breast cancer received 0.2, 0.5, or 0.8&#xa0;μg/kg of DEX or 0.9% normal saline as the control. Baseline (T₀) and on day 1 (T₁), day 2 (T₂), and day 3 (T₃) after the operation, cytokine ELISA was used to determine the effects of DEX on the neural system, stress response, and inflammation. POD incidence was finally determined after treatment with various DEX doses.</p> Results <p>The serum levels of S100β and NSE, norepinephrine and cortisol, IL-1β, IL-6, and TNF-α after treatment with 0.8&#xa0;μg/kg DEX were significantly reduced compared to the control group. The POD incidences following treatment with 0.5 and 0.8&#xa0;μg/kg DEX groups were comparable but significantly lower compared to the control group.</p> Conclusions <p>The DEX effect in POD down-regulation is dose-dependent. DEX (0.8&#xa0;μg/kg) effectively reduces POD incidence in elderly patients undergoing radical mastectomy for breast cancer by inhibiting the production of pro-inflammatory cytokines.</p> <p>Registry: Chinese Clinical Trial Registry, ChiCTR2500101907. Registration date: 6th, May, 2025.</p>