Nature-based solutions (NBS) are a promising and innovative approach to address multiple sustainability challenges faced by cities. Yet, NBS are not integrated into mainstream urban development practices. Based on a qualitative comparative case study of Germany, Hungary, the Netherlands, Spain, Sweden, and the United Kingdom, this study shows how barriers to mainstreaming urban NBS are shaped by the structural conditions in urban infrastructure regimes, which offers an improved, context-sensitive understanding of why such barriers persist. We identify underlying structural conditions shaping seven key barriers to urban NBS: limited collaborative governance, knowledge, data and awareness challenges, low private sector engagement, competition over urban space, insufficient policy development, implementation and enforcement, insufficient public resources, and challenging citizen engagement. This study also advances an understanding of urban infrastructure regimes as complex, heterogeneous systems, made up of different functional domains that define the space available for sustainability innovations. Importantly, our case comparison reveals that similar barriers to NBS mainstreaming in planning processes are caused by different structural conditions across countries. For example, perceived causes of limited citizen engagement are low environmental awareness in Spain, a lack of resources to support participation in Hungary, and NIMBY-ism in the Netherlands. Our findings stress the importance of moving beyond ‘silver bullet’-type approaches to addressing NBS mainstreaming barriers, towards systemic but context-sensitive responses, tailored to specific urban infrastructure regimes. This systematic understanding of barriers and their underlying structural conditions can help both scholars and practitioners identify promising pathways for the mainstreaming of NBS as an urban sustainability innovation.