Background A multi-criteria decision analysis (MCDA) approach has been suggested for helping purchasers in low- and middle-income countries in an evidence-based assessment of multi-source pharmaceuticals to mitigate potential adverse consequences of price-based decisions on patient access to effective medicines. Six workshops for developing MCDA-instruments for purchasing were conducted in Indonesia, Kazakhstan, Thailand, and Kuwait in 2017–2020. In Indonesia and Thailand, two pilot-initiatives aimed to implement the instruments for hospital drug purchasing decisions. Objective By analysing and comparing the experiences and progress from the MCDA-workshops and the two case-examples for hospital implementation in Indonesia and Thailand, we aim to gain insights, which will support future implementation. Methods The selection of criteria and their average weight were compared quantitatively across the MCDA-instruments developed in all four countries and settings. Implementation experiences from two case-examples were studied, which included (1) testing the instrument across a variety of drugs in seven hospitals in Thailand and (2) implementation in one specialty hospital in Indonesia. Semi-structured interviews were conducted via web-conferences with four diverse stakeholders in the pilot implementation projects in Thailand and Indonesia. The open responses were evaluated through qualitative content analysis and synthesis using grounded theory coding. Results Drivers for implementation were making ‘better’ decisions, achieving transparency and a rational selection process, reducing drug shortages, and assuring consistent quality. Challenges were seen on the technical level (definition or of criteria, scoring methods, access to data) or change-related challenges (resistance, perception of increased workload, lack of competencies or capabilities, lack of resources). The comparison of the MCDA instruments revealed high similarity, but also clear need for local adaptations in each specific case. Conclusion A set a of measures targeting challenges related to utility, methodology, data requirements, capacity building and training as well as the broader societal impact can help to overcome challenges in the implementation. Careful planning of implementation and organizational change is recommended for ensuring commitment and fit to local context and culture. Designing a collaborative change program for each application of MCDA-based purchasing will enable healthcare stakeholders to maximally benefit in terms of quality and effectiveness of care and access for patients.