Abstract Background The BRANCH Consortium recently conducted 10 mixed-methods case studies to investigate the provision of health and nutrition interventions for women and children in conflict-affected countries, aiming to better understand the dominant influences on humanitarian health actors’ programmatic decision-making and how such actors surmount intervention delivery barriers. In this paper, the research challenges encountered and the mitigating strategies employed by the case study investigators in four of the BRANCH case study contexts are discussed: Somalia, Mali, Pakistan and Afghanistan. Discussion Many of the encountered research challenges were anticipated, with investigators adopting mitigation strategies in advance or early on, but others were unexpected, with implications for how studies were ultimately conducted and how well the original study aims were met. Insecurity was a fundamental challenge in all study contexts, with restricted geographical access and concerns for personal safety affecting sampling and data collection plans, and requiring reliance on digital communications, remote study management, and off-site team meetings wherever possible. The need to navigate complex local sociopolitical contexts required maximum reliance on local partners’ knowledge, expertise and networks, and this was facilitated by early engagement with a wide range of local study stakeholders. Severe lack of reliable quantitative data on intervention coverage affected the extent to which information from different sources could be triangulated or integrated to inform an understanding of the influences on humanitarian actors’ decision-making. Conclusion Strong local partners are essential to the success of any project, contributing not only technical and methodological capacity but also the insight needed to truly understand and interpret local dynamics for the wider study team and to navigate those dynamics to ensure study rigour and relevance. Maintaining realistic expectations of data that are typically available in conflict settings is also essential, while pushing for more resources and further methodological innovation to improve data collection in such settings. Finally, successful health research in the complex, dynamic and unpredictable contexts of conflict settings requires flexibility and adaptability of researchers, as well as sponsors and donors.