Background: Electroconvulsive therapy (ECT) is a commonly used alternative for treatment-resistant depression (TRD). Although esketamine has a rapid pharmacological antidepressant action, it has not been studied as an ECT anesthetic. The objective of this study was to compare the efficacy and safety of esketamine with propofol when both are used as ECT anesthetic agents. Methods: Forty patients with TRD were assigned to one of two arms in a double-blind, randomized controlled trial: esketamine or propofol anesthesia for a series of eight ECT sessions. Using a non-inferiority design, the primary outcome was the reduction in HAMD-17 depressive symptoms. The other outcomes were: rates of response and remission, anxiety, suicidal ideation, cognitive function, and adverse events. These were compared in an intention-to-treat analysis. Results: Esketamine-ECT was non-inferior to propofol-ECT for reducing TRD symptoms after 8 sessions (adjusted Δ = 2.0, 95 % CI: −1.2–5.1). Compared to propofol-ECT, esketamine-ECT also had higher depression response (80 % vs. 70 %; p =.06) and remission (65 % vs. 55 %; p =.11) rates but non-inferiority was not established. In four components of cognitive function (speed of processing, working memory, visual learning, and verbal learning) esketamine-ECT was non-inferior to propofol-ECT. The results for anxiety, suicidal ideation, and adverse events (all p's >.05) were inconclusive. Conclusion: Esketamine was non-inferior to propofol when both are used as anesthetics for TRD patients undergoing ECT. Replication studies with larger samples are needed to examine the inconclusive results. Registration number: ChiCTR2000033715.