OBJECTIVES: Delirium is a serious complication following neurosurgical procedures. We hypothesise that the beneficial effect of music on a combination of delirium-eliciting factors might reduce delirium incidence following neurosurgery and subsequently improve clinical outcomes. DESIGN: Prospective randomised controlled trial. SETTING: Single centre, conducted at the neurosurgical department of the Erasmus Medical Center, Rotterdam, the Netherlands. PARTICIPANTS: Adult patients undergoing craniotomy were eligible. INTERVENTIONS: Patients in the intervention group received preferred recorded music before, during and after the operation until day 3 after surgery. Patients in the control group were treated according to standard of clinical care. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was presence or absence of postoperative delirium within the first 5 postoperative days measured with the Delirium Observation Screening Scale (DOSS) and, in case of a daily mean score of 3 or higher, a psychiatric evaluation with the latest Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria. Secondary outcomes included anxiety, heart rate variability (HRV), depth of anaesthesia, delirium severity and duration, postoperative complications, length of stay and location of discharge. RESULTS: We enrolled 189 patients (music=95, control=94) from July 2020 through September 2021. Delirium, as assessed by the DOSS, was less common in the music (n=11, 11.6%) than in the control group (n=21, 22.3%, OR:0.49, p=0.048). However, after DSM-5 confirmation, differences in delirium were not significant (4.2% vs 7.4%, OR:0.47, p=0.342). Moreover, music increased the HRV (root mean square of successive differences between normal heartbeats, p=0.012). All other secondary outcomes were not different between groups. CONCLUSION: Our results support the efficacy of music in reducing the incidence of delirium after craniotomy, as found with DOSS but not after DSM-5 confirmation, substantiated by the effect of music on preoperative autonomic tone. Delirium screening tools should be validated and the long-term implications should be evaluated after craniotomy. TRIAL REGISTRATION NUMBER: Trialregister.nl: NL8503 and ClinicalTrials.gov: NCT04649450.