Active conflict settings constitute challenging operating environments for humanitarian health organisations and workers. An emerging feature of some conflicts is direct violence against health workers, facilities, and patients. Since the start of the war in 2011, Syria has endured extreme and deliberate violent attacks on health facilities and workers. This paper reports on the findings from a qualitative study that examined the lived experiences of Syrian humanitarian health workers facing extreme ethical challenges and coping with moral distress. In-depth interviews were carried out with 58 front-line health workers in north-western and southern Syria. Participants described a number of ethical and operational challenges experienced while providing services in extreme conditions, as well as strategies used to deal with them. The complex intersection of personal and organisational challenges is considered and findings are linked to key ethical and humanitarian principles. Both practical recommendations and action steps are provided to guide humanitarian health organisations.