Despite their protection under international law, attacks against health care facilities and workers occur with alarming frequency. During the war in Syria alone, more than 500 attacks have occurred against hospitals. The effects of these attacks devastatingly deprive access to health care for local populations, harm or kill health care workers, and disrupt core social institutions. Individuals and aid organizations working in these settings of extreme violence experience profoundly difficult choices, ranging from how to maintain an acceptable standard of care amidst chaos to whether to rebuild facilities in the same place (at risk of repeat attacks) or in a remote one (at risk of reducing accessibility to people in need). Here, we report findings from a multi-year project examining ethical challenges faced by health care workers and aid organizations operating in Syria. Through a systematic literature review, semi-structured interviews, and in-country workshops, our project described the full range of ethical challenges experienced in settings of extreme violence. These challenges were categorized according to eight core ethical obligations. Our analysis found areas of overlap, tension, and mutual reinforcement between the humanitarian principles to which humanitarian organizations are committed (i.e., neutrality, impartiality, humanity, and independence) and these ethical obligations. Our research suggests that, by incorporating ethical principles and frameworks for ethical decision-making, organizations operating in settings of extreme violence can find novel ways of fulfilling core humanitarian principles and managing the moral distress inherent in these settings. Five recommendations are proposed for how humanitarian organizations could operationalize ethical decision-making.