Following the recent global health crises, such as the 2014 Ebola and 2016 ZIKA outbreaks, the international health community’s ability to deal with such threats has been debated. Amid discussions of how international health security (IHS) and related national health systems should and could be strengthened, the potential of harnessing the role of civil society organizations (CSOs) for more effective responses has been frequently raised. Such participation is often based on the notion that CSOs by their grassroots presence can more effectively help to address health security and health systems challenges in affected populations and communities. Using the World Health Organization’s (WHO) health systems’ building blocks as an evaluative framework, this chapter examines CSOs’ roles and responsibilities during the 2014–2016 West Africa Ebola Outbreak and how they can be further empowered to perform these functions. The chapter draws conclusions about the opportunities and challenges CSOs represent for strengthening IHS and national health systems during public health emergencies in low- and middle-income countries (LMICs).