The spatial distribution and depth of permafrost are changing in response to warming and landscape disturbance across northern Arctic and boreal regions. This alters the infiltration, flow, surface and subsurface distribution, and hydrologic connectivity of inland waters. Such changes in the water cycle consequently alter the source, transport, and biogeochemical cycling of aquatic carbon (C), its role in the production and emission of greenhouse gases, and C delivery to inland waters and the Arctic Ocean. Responses to permafrost thaw across heterogeneous boreal landscapes will be neither spatially uniform nor synchronous, thus giving rise to expressions of low to medium confidence in predicting hydrologic and aquatic C response despite very high confidence in projections of widespread near-surface permafrost disappearance as described in the 2019 Intergovernmental Panel on Climate Change Special Report on the Ocean and Cryosphere in a Changing Climate: Polar Regions. Here, we describe the state of the science regarding mechanisms and factors that influence aquatic C and hydrologic responses to permafrost thaw. Through synthesis of recent topical field and modeling studies and evaluation of influential landscape characteristics, we present a framework for assessing vulnerabilities of northern permafrost landscapes to specific modes of thaw affecting local to regional hydrology and aquatic C biogeochemistry and transport. Lastly, we discuss scaling challenges relevant to model prediction of these impacts in heterogeneous permafrost landscapes.