Abstract Background Older nursing home residents with dementia are commonly prescribed antidepressants despite limited evidence of clinical effect and a high risk of side effects. Deprescribing can be challenging and is often not attempted. The aim of the study is to investigate the effect of a multifaceted intervention targeting nursing home general practitioners and their collaboration with the nursing home staff on the reduction of antidepressant medication in older nursing home residents with dementia. Method The study is a cluster-randomized, non-blinded, controlled trial. General practitioners working as nursing home physicians in the Capital Region of Denmark were recruited between June 1 and October 1, 2021. Eligible participants were individuals with dementia (diagnosed or suspected), ≥ 72 years old, receiving one or more antidepressants, and living in a nursing home with the associated nursing home physician. The complex intervention consisted of three main parts: 1) a training session occurring in the nursing home, 2) a pre-visit reflection tool, and 3) a dialog tool used during a structured home visit at the nursing home. The control group received enhanced care as usual. Primary outcome was the reduction of the total defined daily dose of antidepressants from pre- to post-intervention in the intervention group, compared to the control group. Secondary outcomes included mortality, changes in other psychotropic medication, hospitalization, and symptoms changes. Results We recruited 21 clusters with 128 eligible participants (62/66 in intervention and control). Four clusters withdrew. Most participants were women, and the median age was 85. They received an average of nine different drugs, and the most commonly prescribed antidepressants were sertraline and mirtazapine. The OR for the reduction of antidepressants in the intervention group versus control was 2.3 (95% CI = 0.84–6.2). Mortality rates were similar between groups. Conclusions The intervention did not significantly reduce antidepressant use among older nursing home residents with dementia. Further optimization and testing in a larger study are needed. Trial registration ClinicalTrials.gov ID NCT04985305, registration date: 2021–08-02.