Over the past two decades, global cities have been addressing climate challenges by transforming their gray infrastructural spaces through climate-adaptive and nature-based regeneration processes. These efforts also aim to tackle local ecological, social, and economic disparities. Despite the prevailing focus on technical and performance-based approaches, research on climate-adaptive, nature-based regeneration of streetscapes remains limited and has yet to significantly influence design-driven approaches to urban regeneration. This paper seeks to address these gaps by emphasizing the importance of spatial dimensions in overcoming current theoretical and operational limitations. It introduces a research experience that aims to leverage the potential of design to promote climate-adaptive, nature-based green regeneration of streetscapes and to integrate this approach into mainstream practices through a “research-by-design” methodology. To achieve this, an operational framework has been developed and is presented here, offering both conceptual and practical insights for creating climate-adaptive, nature-based streetscapes. Following the proposed methodology, two pilot design cases are introduced and discussed, both located in the Italian city of Matera: Piccianello and La Martella. This iterative process aims to establish a framework for sustainable, long-term urban resilience, making cities greener, more adaptive, and more equitable.