The article explores the challenges encountered during the formation of the Baltic macro-region comprising Russia and eight EU countries (Germany, Poland, Sweden, Denmark, Finland, Lithuania, Latvia and Estonia) in the context of the ongoing geopolitical and geo-economic changes. The article aims to assess the dynamics, level, structure and pace of economic development of three Russian regions located on the Baltic Sea (St. Petersburg, Leningrad and Kaliningrad regions) and analyse the intensity of their trade relations with countries of the macro-region. Russian Baltic regions have higher development rates compared to the national average. However, they experience difficulties in their economic development resulting from negative external factors. The article describes possible ways of overcoming these difficulties by improving the sectoral structure of the economy and diversifying international ties. In this context, the development of inter-regional cooperation and the formation of a spatially distributed territorial socio-economic system, including the three Russian Baltic regions, will be particularly beneficial. The period covered by the article is 1996—2021, with a special focus on 2014—2021. The study is based on the economic and statistical analysis of official data of Rosstat and the Federal Customs Service on the sectoral structure and dynamics of the gross regional product (GRP), volume and changes in foreign trade, and its commodity and geographical structure.