BACKGROUND: In South Sudan, the civil war in 2016 led to mass displacement in Juba that rapidly spread to other regions of the country. Access to health care was limited because of attacks against health facilities and workers and pregnant women and newborns were among the most vulnerable. Translation of newborn guidelines into public health practice, particularly during periods of on-going violence, are not well studied during humanitarian emergencies. During 2016 to 2017, we assessed the delivery of a package of community- and facility-based newborn health interventions in displaced person camps to understand implementation outcomes. This case analysis describes the challenges encountered and mitigating strategies employed during the conduct of an original research study. DISCUSSION: Challenges unique to conducting research in South Sudan included violent attacks against humanitarian aid workers that required research partners to modify study plans on an ongoing basis to ensure staff and patient safety. South Sudan faced devastating cholera and measles outbreaks that shifted programmatic priorities. Costs associated with traveling study staff and transporting equipment kept rising due to hyperinflation and, after the July 2016 violence, the study team was unable to convene in Juba for some months to conduct refresher trainings or monitor data collection. Strategies used to address these challenges were: collaborating with non-research partners to identify operational solutions; maintaining a locally-based study team; maintaining flexible budgets and timelines; using mobile data collection to conduct timely data entry and remote quality checks; and utilizing a cascade approach for training field staff. CONCLUSIONS: The case analysis provides lessons that are applicable to other humanitarian settings including the need for flexible research methods, budgets and timelines; innovative training and supervision; and a local research team with careful consideration of sociopolitical factors that impact their access and safety. Engagement of national and local stakeholders can ensure health services and data collection continue and findings translate to public health action, even in contexts facing severe and unpredictable insecurity.