International science and technology (S&T) cooperation is one of the important ways to ensure the continuous development of a national innovation system. “One Belt One Road” advocates the concepts of common business, common construction, and sharing, and new countries and regions are constantly added. However, different countries/regions have different natural and socio-economic characteristics, so the main controlling factors affecting their international S&T cooperation may not be the same. Therefore, this paper uses a combination of multi-source data and multiple methods to collectively construct an assessment model of the driving effect of international S&T cooperation in Xinjiang. The evaluation results of the entropy-weighted TOPSIS model show that the contributions of S&T level, city nature, and S&T investment to international S&T cooperation in Xinjiang are 22.9%, 22.3%, and 20.4%, respectively. Singapore, Germany, and Russia are the top three countries in terms of the effectiveness of international S&T cooperation with Xinjiang. The results of the STIRPAT model show that the total number of R&D personnel and the number of R&D personnel per 1000 workers are the main factors affecting the driving effect of international S&T cooperation. The former can be regarded as the stabilizer of international S&T cooperation. This paper’s findings can provide theoretical support for the efficient integration of diverse advantageous resources among cooperating subjects.