The transition towards a sustainable circular economy (CE) model is seen as a solution to keep the consumption of the earth’s resources within planetary boundaries. In the regional context, the CE is promoted through various policy actions, one being the smart specialisation concept. This paper provides a novel approach to examining the spatial adaption of a CE through a conceptual framework of research and innovation strategies for smart specialisation (S3) in Europe. This interdisciplinary research presents a multi-country comparison of S3 implementation in Europe in 12 regions that have defined the CE as a priority area. The data consist of interviews with representatives of organisations responsible for the regional S3 process. The findings indicate that a political demand exists for proceeding further with the construction of transformative activities involving the CE, but the models and stages of implementation vary. In addition, most regions still struggle with building specific monitoring and evaluation measures and mechanisms for the CE. Despite these challenges, promoting the CE as a strategic priority through the S3 process has, at least in some regions, helped define the CE targets and actions by focusing on existing regional assets and future potential.