Background: Police and mental health co-responder programs operate internationally and can be effective in providing timely and appropriate assessment, brief intervention, and referral services for people experiencing mental health crises. However, these models vary greatly, and little is known about how the design and implementation of these programs impacts their effectiveness. Method: This study was a qualitative, post hoc implementation determinant evaluation of mental health co-responder units in Brisbane, Australia, comprising of verbal or written interviews with police and mental health staff with an on-road role in the co-responder units, and their managers. The Consolidated Framework for Implementation Research was used to identify barriers and enablers to the program's implementation and effectiveness. Results: Participants (n = 30) from all groups felt strongly that the co-responder units are a substantial improvement over the usual police management of mental health crisis cases, and lead to better outcomes for consumers and the service. Enablers included an information-sharing agreement; the Mental Health Co-Responder (MHCORE) program's compatibility with existing police and mental health services; and the learning opportunity for both organizations. Barriers included cultural differences between the organizations, particularly risk-aversion to suicidality for police and a focus on least-restrictive practices for health; extensive documentation requirements for health; and a lack of specific mental health training for police. Conclusions: Using an evidence-based implementation science framework enabled identification of a broad range of contextual barriers and enablers to implementation of police mental health co-responder programs. Adapting the program to address these barriers and enablers during the planning, implementation, monitoring, and evaluation phases increases the likelihood of the service's effectiveness. These findings will inform the spread and scale of the co-responder program across Queensland, and will be relevant to police districts internationally considering implementing a co-responder program.