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Drylands face urgent development challenges that are complex and interconnected, requiring holistic systems-based approaches. Here, we present a social–ecological systems framework to guide research, policy, and action across disciplines and sectors towards sustainability transformations in drylands for improved livelihoods and enhanced ecosystem, livestock, and human health. Our conceptual framework integrates three non-exclusive and complementary lenses of human-driven transformations: systemic, structural and enabling/grassroots change. Based on these three complementary lenses, along with three main phases of transformation and key associated actions, we briefly illustrate the framework’s value through the case of the Karamoja cross-border region of East Africa. We show how the framework can be used as an entry point to identify and analyse key challenges and their interlinkages; envision desired social–ecological systems; and explore pathways towards sustainability. The framework provides actionable guidance to co-develop context-specific interventions that support sustainability transformations in drylands.