Russian and foreign specialists continue to maintain their research interest in the Eastern Mediterranean, both in view of the energy potential of the region as well as unresolved security issues. This article considers the role of global powers – Russia and the United States – in the Eastern Mediterranean from the point of view of the theory of the regional security complex. An attempt was made to determine the interests and priorities of Moscow and Washington on the basis of an analysis of the doctrinal approaches of both states in the identified subcomplex. Approaches of the two states to the Syrian issue were analyzed as well. The subordination of the “Syrian portfolio” to other policy issues of Russia and the United States is shown, as well as global powers’ policy evolution towards this key crisis for world politics. Despite the strategic desire to stabilize the region and exit from regional conflicts, Russia and the United States retain interests that will require their presence, albeit limited. The article indicates the influence of the states of other sub-complexes of the Middle East regional security, primarily the Persian Gulf, on the Levant and, more broadly, the mesoregion of the Eastern Mediterranean, as well as the growing weight of regional powers in general.