The study examined the impact of United States-Russia relations on humanitarian crises in Syria between 2011 and 2020. Anchored on structural-realist theory, documentary method of data collection and qualitative content analysis, the study interrogated the interconnections between the strategies of interventions by big powers and humanitarian crises in Syria. The study noted that the conflicting national interests of big powers, notably the United States and Russia and their allies are fuelling the Syrian conflict, with serious implication for humanitarian crisis. It thus underscored the need for a reset in US-Russia relations to foster and sustain deeper co-operation between the two great powers and their allies. To mitigate the human suffering and misery attendant to the spiral conflict in Syria, the study opines that the United States and Russia should relinquish their zero-sum game posture and embrace a negotiated solution involving a compromise by conflicting parties on the basis of mutual consent. Keywords: US-Russia relations, Syrian conflict, Big Powers, Humanitarian Crisis, National Interest..