With the global economy integration and progress in energy transformation, it has become a general trend to surpass national boundaries to achieve wider and optimal energy resource allocations. Consequently, there is a critical need to adopt scientific approaches in assessing cross-border power grid interconnection projects. First, considering the promotion of large-scale renewable energy resources and improvements in system adequacy, a comprehensive assessment index system, including costs, socio-economic benefits, environmental benefits, and technical benefits, is established in this study. Second, a synthetic assessment framework is proposed for cross-border power grid interconnection projects based on the index system comprising cost-benefit analysis, with market and network simulations, iterative methods for indicator weight evaluation, and technique for order preference by similarity to an ideal solution (TOPSIS) method for the project rankings. Finally, by assessing and comparing three cross-border projects between Europe and Asia, the proposed index system and assessment framework have been proved to be effective and feasible; the results of this system can thus support investment decision-making related to such projects in the future.