This paper presents major gaps and challenges for implementing the UN Decade of Ocean Science for Sustainable Development (2021-2030) in the Mediterranean region. The authors make recommendations on the scientific knowledge needs and co-design actions identified during two consultations, part of the Decade preparatory-phase, framing them in the Mediterranean Sea’s unique environmental and socio-economic perspectives. According to the ‘Mediterranean State of the Environment and Development Report 2020’ by the United Nations Environment Programme Mediterranean Action Plan and despite notable progress, the Mediterranean region is not on track to achieve and fully implement the Sustainable Development Goals of Agenda 2030. Key factors are the cumulative effect of multiple human-induced pressures that threaten the ecosystem resources and services in the global change scenario. The basin, identified as a climate change vulnerability hotspot, is exposed to pollution and rising impacts of climate change. This affects mainly the coastal zones, at increasing risk of extreme events and their negative effects of unsustainable management of key economic assets. Transitioning to a sustainable blue economy is the key for the marine environment’s health and the nourishment of future generations. This challenging context, offering the opportunity of enhancing the knowledge to define science-based measures as well as narrowing the gaps between the Northen and Southern shores, calls for a joint (re)action. The paper reviews the state of the art of Mediterranean Sea science knowledge, sets of trends, capacity development needs, specific challenges, and recommendations for each Decade’s societal outcome. In the conclusions, the proposal for a Mediterranean regional programme in the framework of the Ocean Decade is addressed. The core objective relies on integrating and improving the existing ocean-knowledge, Ocean Literacy, and ocean observing capacities building on international cooperation to reach the “Mediterranean Sea that we want”.