Environmental degradation has become one of the major obstacles to sustainable development and human well-being internationally. Scientific efforts are being made to understand the mechanism of environmental degradation and sustainability. Critical Zone (CZ) science and research on the multi-functional landscape are emerging fields in Earth science that can contribute to such scientific efforts. This paper reviews the progress, similarities and current status of these two scientific research fields, and identifies a number of opportunities for their synergistic integration through functional and multi-functional approaches, process-based monitoring, mechanistic analyses and dynamic modeling, global long-term and networked monitoring and systematic modeling supported by scaling and deep coupling. These approaches proposed in this paper have the potential to support sustainable human well-being by strengthening a functional orientation that consolidates multi-functional landscape research and CZ science. This is a key challenge for sustainable development and human well-being in the twenty-first century.