Background: Tele-rehabilitation has grown significantly in the past years, especially in 2020 when it has been a crucial tool for supporting patients during the COVID-19 pandemic. Within the context of tele-rehabilitation, serious games have a significant role. However, realizing software for serious games capable of responding to the variety of user needs is resource demanding. Methods: we present Proteo, a modular framework for developing serious games from scratch, but with the ability of providing a high-level interface for game customization by therapists and researchers. We also present two serious game implementation examples with analysis of end user’s and therapists/researchers’ satisfaction. Results: by involving a group of 11 specialized therapists and 9 end users we analyzed the Proteo user’s satisfaction. We found that therapists and end users scored high level of involvement, and the therapists scored also high level of suitability. More in depth, both groups showed significant differences between positive and negative feeling, with positive feeling scoring higher than negative ones. Finally, concerning Users’ level of suitability the condition of successfulness of the system, ability to control, clarity and helpfulness were reported as high while the difficulty of the system and the difficulty of the task were reported as low. Conclusions: the proposed framework is a step forward in providing a comprehensive open-source, modular framework, to develop serious games for tele-rehabilitation. Proteo is distributed with a MIT license and available to researchers on GitHub and has been well accepted by the users we involved in the evaluation tests.