Globally, drylands represent the largest terrestrial biome and are projected to expand by 23% by the end of this century. Drylands are characterized by extremely low levels of water and nutrients and exhibit highly heterogeneous distribution in plants and biocrusts which make microbial processes shaping the dryland functioning rather unique compared with other terrestrial ecosystems. Nitrous oxide (N2O) is a powerful greenhouse gas with ozone depletion potential. Despite of the pivotal influences of microbial communities on the production and consumption of N2O, we have limited knowledge of the biological pathways and mechanisms underpinning N2O emissions from drylands, which are estimated to account for 30% of total gaseous nitrogen emissions on Earth. In this article, we describe the key microbial players and biological pathways regulating dryland N2O emissions, and discuss how these processes will respond to emerging global changes such as climate warming, extreme weather events and nitrogen deposition. We also provide a conceptual framework to precisely manipulate the dryland microbiome to mitigate N2O emissionsin situusing emerging technologies with great specificity and efficacy. These cross-disciplinary efforts will enable the development of novel and environmental-friendly microbiome-based solutions to future mitigation strategies of climate change.