Health Technology Assessment (HTA) in Europe has undergone significant evolution, culminating in the adoption of Regulation (EU) 2021/2282 on HTA (HTAR) aimed at fostering sustainable collaboration in HTA at the European Union (EU) level. The EUnetHTA 21 project, a 2-year initiative, was commissioned to address key methodological issues and prepare for the implementation of the HTAR. This commentary documents the outcomes of the EUnetHTA 21 project, focusing on Joint Clinical Assessments (JCAs), while analyzing challenges encountered and lessons learned for future collaboration under the HTAR. The EUnetHTA 21 consortium, comprising thirteen European HTA bodies, developed twenty guidance documents and thirteen templates, refining methods and procedures for joint work in HTA at EU level. Pilot JCAs and Joint Scientific Consultations were conducted to test these materials. Lessons learned from this experience emphasize the importance of inclusive consensus building, effective time and resource management, capacity building, and continuous quality improvement. The project’s realization underscores a collective commitment among HTA bodies to continue to collaborate, now under a legal framework. Recommendations from the project, along with experiences gained from previous European Network for HTA (EUnetHTA) Joint Actions, provide a foundation for developing guidance for EU-HTA under the HTAR. Further proactive efforts at national and central levels are essential to coordinate and ensure a sustainable cooperation. The EUnetHTA 21 experience provides valuable insights for advancing cooperation in HTA under the HTAR, aiming to improve the quality of HTA, avoid duplication, and ultimately enhance patient access to safe and effective health technologies in the EU.