Cross-border interactions of people contribute to the (re)production of functional cross-border regions, yet they remain underexplored. We have addressed this by proposing a conceptual framework stemming from the mobility approach and mobile big data. Using geolocated social media data as a proof-of-concept, we empirically examined people’s mobilities across all the internal border regions in Europe. We distinguished between cross-border regions by their interaction characteristics regarding temporal rhythms of cross-border mobilities, and used their spatial extent to reimagine functional cross-border regions. This approach is of benefit to research and practice for policy and planning for border regions, and to understand their territorial cohesion better.