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BACKGROUND Dexmedetomidine is known to be a sedative. Recent studies suggest that administration of dexmedetomidine can prevent postoperative delirium (POD) which has been confirmed as a common complication after major surgery. However, its effects in patients undergoing oesophagectomy are scarce. OBJECTIVE To investigate the efficacy and safety of dexmedetomidine in reducing POD in elderly patients after transthoracic oesophagectomy with total intravenous anaesthesia (TIVA). DESIGN A randomised, double-blind, placebo-controlled trial. SETTING Single-centre, tertiary care hospital, November 2016 to September 2018. PATIENTS Eligible patients (n = 177) undergoing transthoracic oesophagectomy were randomly assigned to receive total intravenous anaesthesia (TIVA, n = 87) or dexmedetomidine with TIVA (DEX-TIVA, n = 90). INTERVENTIONS Patients receiving DEX-TIVA received a loading dose of dexmedetomidine (0.4 μg kg−1), over 15 min, followed by a continuous infusion at a rate of 0.1 μg kg−1 h−1 until 1 h before the end of surgery. Patients receiving TIVA received physiological saline with a similar infusion rate protocol. OUTCOME MEASURES The primary outcome was the incidence of POD. The secondary endpoints were the incidence of emergence agitation, serum interleukin-6 (IL-6) levels and haemodynamic profile. RESULTS All randomised patients were included with planned intention-to-treat analyses for POD. Delirium occurred in 15 (16.7%) of 90 cases given dexmedetomidine, and in 32 (36.8%) of 87 cases given saline (P = 0.0036). The DEX-TIVA group showed less frequent emergence agitation than the TIVA group (22.1 vs. 48.0%, P = 0.0058). The incremental change in surgery-induced IL-6 levels was greater in the TIVA group than DEX-TIVA group (P < 0.0001). CONCLUSION Adding peri-operative dexmedetomidine to a total intravenous anaesthetic safely reduces POD and emergence agitation in elderly patients undergoing open transthoracic oesophagectomy. These benefits were associated with a postoperative reduction in circulating levels of the pro-inflammatory cytokine IL-6 and stabilisation of the haemodynamic profile. TRIAL REGISTRATION Chinese Clinical Trials Register Identifier: ChiCTR-IPR-17010881.