Smallholders are crucial for global sustainability given their importance to food and nutritional security, agriculture, and biodiversity conservation. Worldwide smallholders are subject to expanded telecoupling whereby their social-ecological systems are linked to large-scale socioeconomic and environmental drivers. The present research uses the synthesis of empirical evidence to demonstrate smallholder telecoupling through the linkages stemming from the global-level integration of markets (commodity, labor, finance), urbanization, governance, and technology. These telecoupling forces are often disadvantageous to smallholders while certain conditions can contribute to the potential sustainability of their social-ecological systems. Case studies were chosen to describe sustainability opportunities and limits involving smallholder production and consumption of high-agrobiodiversity Andean maize amid telecoupled migration (Bolivia), the role of international eco-certification in smallholder coffee-growing and agroforests (Colombia), smallholder organic dairy production in large-scale markets and technology transfer (upper Midwest, U.S.A.), and smallholders' global niche commodity production of argan oil (Morocco). These case studies are used to identify the key challenges and opportunities faced by smallholders in telecoupling and to develop a conceptual framework. This framework specifies the integrated roles of global systems together with influential public and private institutions operating at multiple scales including the national level. The framework also integrates the local dynamics of smallholders' multiple land use units and their socioeconomic and environmental variation. Spatial spillover effects in smallholder landscapes are an additional element. This framework further establishes the un-Romantic, nonteleological, and antifetishistic view of smallholders. It provides specific insights on the multilevel dynamics of smallholder telecoupling and potential sustainability opportunities that can strengthen livelihoods, biodiversity conservation, and food and nutritional security. These insights are concluded to be valuable to environmental, agricultural, and food scientists and scholars (both biogeophysical sciences and social sciences), policy makers, institutional analysts, development specialists and practitioners, social justice activists, and others seeking to advance global sustainability including sustainable development.