The Belt and Road Initiative (BRI) serves as China’s blueprint and major strategy for opening-up in the new era. This study theoretically examines three mechanisms of the ‘21st Century Maritime Silk Road’ (CMSR) to promote the opening up of provinces and cities along the line, including the allocation, integration, and circulation mechanisms. Using 2009–2021 data from prefecture-level cities, this study designed a quasi-natural experiment based on the CMSR by combining propensity score matching (PSM) and differences-in-differences (DID) methods. The study findings show CMSR significantly promoted China’s opening-up. Various robustness tests demonstrate that our findings are robust. Mechanism analysis shows that CMSR improved China’s opening-up by promoting the flow of production factors, integrating domestic and international product markets, and accelerating circulation. Heterogeneity analysis shows that CMSR strongly influences large, coastal, and nonprovincial cities. These findings provide a new perspective for evaluating the policy effects of the 21st CMSR.