INTRODUCTION: Ten years of conflict has displaced more than half of Northwest Syria's (NWS) population and decimated the health system, water and sanitation, and public health infrastructure vital for infectious disease control. The first NWS COVID-19 case was declared on July 9, 2020, but impact estimations in this region are minimal. With the rollout of vaccination and emergence of the B.1.617.2 (Delta) variant, we aimed to estimate the COVID-19 trajectory in NWS and the potential effects of vaccine coverage and hospital occupancy. METHODS: We conducted a mixed-method study, primarily including modeling projections of COVID-19 transmission scenarios with vaccination strategies using an age-structured, compartmental susceptible-exposed-infectious-recovered (SEIR) model, supported by data from 20 semi-structured interviews with frontline health workers to help contextualize interpretation of modeling results. RESULTS: Modeling suggested that existing low stringency non-pharmaceutical interventions (NPIs) minimally affected COVID-19 transmission. Maintaining existing NPIs after the Delta variant introduction is predicted to result in a second COVID-19 wave, overwhelming hospital capacity and resulting in a fourfold increased death toll. Simulations with up to 60% vaccination coverage by June 2022 predict that a second wave is not preventable with current NPIs. However, 60% vaccination coverage by June 2022 combined with 50% coverage of mask-wearing and handwashing should reduce the number of hospital beds and ventilators needed below current capacity levels. In the worst-case scenario of a more transmissible and lethal variant emerging by January 2022, the third wave is predicted. CONCLUSION: Total COVID-19 attributable deaths are expected to remain relatively low owing largely to a young population. Given the negative socioeconomic consequences of restrictive NPIs, such as border or school closures for an already deeply challenged population and their relative ineffectiveness in this context, policymakers and international partners should instead focus on increasing COVID-19 vaccination coverage as rapidly as possible and encouraging mask-wearing.