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Abstract Background In 2014, nursing home administration and government officials were facing increasing public and media scrutiny around the variation of antipsychotic medication (APM) prescribing across Ontario nursing homes. In response, policy makers partnered to test an academic detailing (AD) intervention to address appropriate prescribing of APM in nursing homes in a cluster-randomized trial. This mixed-methods study aimed to explore how and why the AD intervention may have resulted in changes in the nursing home context. The objectives were to understand how the intervention was implemented, explore contextual factors associated with implementation, and examine impact of the intervention on prescribing. Methods Administrative data for the primary outcome of the full randomized trial will not be available for a minimum of 1 year. Therefore, this paper reports the findings of a planned, quantitative interim trial analysis assessed mean APM dose and prescribing prevalence at baseline and 3 and 6 months across 40 nursing homes (18 intervention, 22 control). Patient-level administrative data regarding prescribing were analyzed using generalized linear mixed effects regression. Semi-structured interviews were conducted with nursing home staff from the intervention group to explore opinions and experiences of the AD intervention. Interviews were analyzed using the framework method, with constructs from the Consolidated Framework for Implementation Research (CFIR) applied as pre-defined deductive codes. Open coding was applied when emerging themes did not align with CFIR constructs. Qualitative and quantitative findings were triangulated to examine points of divergence to understand how the intervention may work and to identify areas for future opportunities and areas for improvement. Results No significant differences were observed in prescribing outcomes. A total of 22 interviews were conducted, including four academic detailers and 18 nursing home staff. Constructs within the CFIR domains of Outer Setting, Inner Setting, and Characteristics of Individuals presented barriers to antipsychotic prescribing. Intervention Source, Evidence Strength and Quality, and Adaptability explained participant engagement in the AD intervention; nursing homes that exhibited a Tension for Change and Leadership Engagement reported positive changes in processes and communication. Conclusions Participants described their experiences with the intervention against the backdrop of a range of factors that influence APM prescribing in nursing homes that exist at the system, facility, provider, and resident levels. In this context, the perceived credibility and flexibility of the intervention were critical features that explained engagement with and potential impact of the intervention. Development of a common language across the team to enable communication was reported as a proximal outcome that may eventually have an effect on APM prescribing rates. Process evaluations may be useful during early stages of evaluation to understand how the intervention is working and how it might work better. Qualitative results suggest the lack of early changes observed in prescribing may reflect the number of upstream factors that need to change for APM rates to decrease. Trial registration ClinicalTrials.gov, NCT02604056