As the world’s largest coordinated network of protected areas, the Natura 2000 network (N2k) encompasses the most valuable and threatened species and habitats in Europe. However, N2k sites have been often criticized due to their rigid management system that focuses only on conservation practice without a strategic vision for linking with the regional plans. This study aims to develop a novel approach for sustainable management of N2k sites in Italy by identifying existing gaps and developing conservation policies. For this purpose, a panorama of the current challenges in the European sites was provided at the first step. Then, the management status of the natural protected sites in Italy was studied by selecting the Umbria Region as the case study. Finally, we develop a strategic approach for boosting the conservation policies and sustainable management of the N2k sites in Italy. The findings highlight that the sustainability of N2k sites requires an inclusive effort in the social, economic, and policymaking fields to meet its conservation objectives. Such an effort encompasses a sophisticated management approach that consists of a network of tools for monitoring the state of conservation, land uses, and socio-economic activities at the regional scale. Furthermore, the integration of environmental policies with regional plans is essential for the sustainable management of the N2k sites.