Purpose It is unclear how the evidence from clinical trials best translates into complex clinical settings. The aim of this quality improvement (QI) project was to change prescribing practice for rapid tranquillization in inpatient mental health care services examining the effectiveness of the Plan-Do-Study-Act (PDSA) method. Methods A prospective QI project was conducted to ensure that intramuscular (IM) diazepam was substituted with IM lorazepam for benzodiazepine rapid tranquillization in inpatient mental health care. We monitored the prescription and administration of medication for rapid tranquillization before ( N = 371), during ( N = 1130) and after ( N = 364) the QI intervention. Seven iterative PDSA cycles with a multiple-component intervention approach were conducted to gradually turn the prescribing practice in the desired direction. Simultaneously, a standard monitoring regimen was introduced to ensure patient safety. Results Lorazepam administrations gradually replaced diazepam during the intervention period which was sustained post-intervention where lorazepam comprised 96% of benzodiazepine administrations for rapid tranquillization. The mean dose of benzodiazepine administered remained stable from pre (14.40 mg diazepam equivalents) to post (14.61 mg) intervention phase. Close to full compliance (> 80%) with vital signs monitoring was achieved by the end of the observation period. Conclusion It was possible to increase the quality of treatment of acute agitation in a large inpatient mental health care setting using a stepwise approach based on iterative PDSA cycles and continuous data feedback. This approach might be valuable in other prescribing practice scenarios with feedback from local stakeholders and opinion leaders.