Abstract Alcohol and other drug misuse are significant but neglected public health issues in conflict-affected populations. In this article, we review the literature on the challenges and strategies for implementing substance misuse treatment and prevention services in conflict and post-conflict settings in low- and middle-income countries. We identified nine studies describing interventions in conflict-affected populations residing in Afghanistan, Croatia, India, Kenya, Kosovo, Pakistan, and Thailand. Six of these nine studies focused on refugee populations. Reports revealed challenges to intervention implementation, as well as promising practices and recommendations for future implementation that we characterized as existing in the inner and outer contexts of an implementing organization. Challenges existing in the outer context included low political prioritization, lack of coordination and integration, and limited advocacy for access to substance misuse services. Challenges within the inner context related to competing priorities and a shortage of providers. Resource limitations existed in both the inner and outer contexts. Stigma was a challenge that threatened implementation and utilization of substance use services in situations when substance use interventions were not congruent with the roles, structure, values, and authority of the system or implementing organization. Future research should focus on developing, applying, and evaluating strategies for overcoming these challenges in order to make progress toward meeting the need for substance misuse services in conflict-affected populations.