This paper defines sustainability of a river basin and further investigated the use of sustainability indicators for integrated assessment of a large river basin. The concept of river sustainability concerns not only the ecological condition of the river course, but also socioeconomic activities in the river basin. River sustainability is concerned with resource sufficiency, resilience to water-related risks, access to water supply and other services, the productive use of water, and fairness between different users and generations. A case study is undertaken to examine the underlying sustainability of the Yellow River in China. The Process Analysis Method is employed for developing a sustainability assessment framework. Through systematic process, a tailored indicator set is selected and categorized under three domains, namely, environmental performance, social wellbeing, and economic development. Extensive fieldwork was carried out in order to conduct stakeholder interviews and collect comprehensive data. The assessment provides policy-makers and river managers with a holistic review of the river basin, which can be used for underpinning integrated river basin management policies.