During the times of the COVID-19 pandemic, nations have issued unprecedented border closures around the world, yielding abrupt impacts on the movement of goods and people. This has heavily affected the quality of life in border regions, which are often found to be at a disadvantage when compared to other regions in terms of employment, accessibility, social services and economic growth. Based upon developing threads in the literature concerning the untapped potential for development in border regions, we argue that the Mission-Oriented Approach (MOA) can fit well with the ambitious goal to revitalize those territories in the aftermath of the pandemic. Despite the surge of MOA in discourses on innovation policy, we seek to implement it in a regional development perspective, pursuing both economic and social policy objectives. The authors unravel the policy concept of MOA into three main aspects: (I) address a sound societal challenge; (II) Research & Development (R&D) regional agenda embedded in a cross-border regional development vision; (III) mobilizing multiple cross-sectorial projects. Through a desk study analysis, the authors draw insights from selected case studies where these aspects have been implemented to inspire policy intervention in the aftermath of COVID-19. This paper presents the MOA theoretical model, which has potential explanatory power in other cross-border regions.