This research is dedicated to analyzing the transformation of cross-border and border cooperation processes in the Kaliningrad region in the context of global geopolitical changes caused by the COVID-19 pandemic and the start of the special military operation in Ukraine. Particular attention is paid to the impact of these factors on the region's economic activity, given its exclave status. The Kaliningrad region, as a geographically isolated region, has proven to be most vulnerable to external restrictions. The imposition of sanctions and restrictions on a number of economic sectors by the European Union has significantly affected the operation of joint ventures with foreign capital and led to the premature termination of a number of cross-border cooperation programs. The article conducts an in-depth analysis of the dynamics of joint venture activities, examines the reasons for the decline in their economic activity, and assesses the scale of losses. Particular attention is paid to evaluating the impact of geopolitical changes on the region's investment climate and its attractiveness to foreign investors. Additionally, the study analyzes the consequences of the premature termination of cross-border cooperation programs funded by the European Union. The contribution of these programs to the region's socio-economic development, the formation of good-neighborly relations, and the strengthening of integration processes is assessed. In the concluding part of the work, the prospects for the development of cross-border and border cooperation in the Kaliningrad region in new geopolitical conditions are considered. The possibilities of reorienting towards new markets and partners are analyzed, as well as the need to develop new mechanisms and tools to maintain economic activity and social development in the region.