The Kaliningrad region is a socio-economically developed area with a steadily increasing population. Its economy is predominantly influenced by manufacturing industries, whose growth is supported by the region’s strategic geographic position on the Baltic coast and the Special Economic Zone (SEZ) regime. However, the region’s exclave status, which makes it reliant on external factors, hinders its development. Any change in these external factors could necessitate a restructuring of manufacturing industries. The severing of former foreign economic and social ties, the discontinuation of cross-border cooperation due to the actions of unfriendly countries, and the imposition of eleven packages of unlawful anti-Russian sanctions have had a more pronounced impact on the regional economy compared to the country’s inland regions. Logistics between the region and the main part of the country have been significantly complicated. Manufacturing industries have faced disruptions in the supply of essential foreign-made semi-finished products. The exports of several regionally-produced goods have been restricted, and transit through the Baltic States has become more difficult. This article aims to assess the impact of these restrictions on the development of manufacturing industries in the region. Another goal is to provide a rationale for the restructuring of specialization and changes in the geography of external relations in these increasingly complex external circumstances. Recommendations based on the findings obtained will contribute to the region’s sustainable development, characterized by dynamic growth and proportional development.