As a new area of science and technology (S&T), big data science and analytics embodies an unprecedentedly transformative power—which is manifested not only in the form of revolutionizing science and transforming knowledge, but also in advancing social practices, catalyzing major shifts, and fostering societal transitions. Of particular relevance, it is instigating a massive change in the way both smart cities and sustainable cities are understood, studied, planned, operated, and managed to improve and maintain sustainability in the face of expanding urbanization. This relates to what has been dubbed data-driven smart sustainable urbanism, an emerging approach that is based on a computational understanding of city systems that reduces urban life to logical and algorithmic rules and procedures, as well as employs a new scientific method based on data-intensive science, while also harnessing urban big data to provide a more holistic and integrated view and synoptic intelligence of the city. This paper examines the unprecedented paradigmatic and scholarly shifts that the sciences underlying smart sustainable urbanism are undergoing in light of big data science and analytics and the underlying enabling technologies, as well as discusses how these shifts intertwine with and affect one another in the context of sustainability. I argue that data-intensive science, as a new epistemological shift, is fundamentally changing the scientific and practical foundations of urban sustainability. In specific terms, the new urban science—as underpinned by sustainability science and urban sustainability—is increasingly making cities more sustainable, resilient, efficient, and livable by rendering them more measurable, knowable, and tractable in terms of their operational functioning, management, planning, design, and development.