This study describes a Pyrenean cross-cultural structure called Centre for the Promotion of Physical Activity and Health (CAPAS-City) that was created to promote physical activity (PA) in Huesca (Spain) and Tarbes (France). The main aim of this centre is to lead the way in the design, implementation, and evaluation of multilevel PA interventions to improve their efficacy and sustainability inside the city. CAPAS-City responds to the main challenges related to multilevel PA interventions, through six guiding principles: (1) promoting sustainability, (2) playing a leadership role, (3) promoting multisectoral partnerships, (4) using evidence-based strategies, (5) promoting integrated knowledge translation, and (6) using a participatory research approach. Five multilevel PA interventions were designed in both cities by CAPAS-City with these principles in mind. Through the example of the Annual MOT Test adapted to bikes, we also illustrate one practical application of the use of these principles, following the Social-Ecological approach, in which the main agents of influence are involved at different levels to encourage cycling. According to the promising results found in this study, CAPAS-City appears to be a structure that is able to respond to the main needs and challenges of multilevel interventions to increase PA levels in the whole population of both cities.