Freshwater ecosystems are declining under climate change and land-use change. To maximize the return on investment in freshwater conservation with limited financial resources, managers must prioritize management actions that are most cost-effective. However, little is known about what these priorities may be under the combined effects of climate and land-cover change. We present a novel decision-making framework for prioritizing conservation resources to different management actions for the conservation of freshwater biodiversity. The approach is novel in that it has the ability to model interactions, rank management options for dealing with conservation threats from climate and land-cover change, and integrate empirical data with expert knowledge. We illustrate the approach using a case study in South East Queensland (SEQ), Australia under climate change, land-cover change and their combined effects. Our results show that the explicit inclusion of multiple threats and costs results in quite different priorities than when costs and interactions are ignored. When costs are not considered, stream and riparian restoration, as a single management strategy, provides the greatest overall protection of macroinvertebrate and fish richness in rural and urban areas of SEQ in response to climate change and/or urban growth. Whereas, when costs are considered, farm/land management with stream and riparian restoration are the most cost-effective strategies for macroinvertebrate and fish conservation. Our findings support riparian restoration as the most effective adaptation strategy to climate change and urban development, but because it is expensive it may often not be the most cost-efficient strategy. Our approach allows for these decisions to be evaluated explicitly.