The aim of this study was to explore the differential relationships between students' science performance and their ICT availability, ICT use, and attitudes toward ICT based on the data from the Program for International Student Assessment (PISA) 2015 across the countries and regions including South/ Latin America, Europe, and Asia and Pacific. Before 2015, the PISA tests were paper-based, but in 2015, for the first time, a computer-based test was used. The mean score in science performance decreased dramatically in PISA 2015. In order to propose a plausible reason for this decrease, the relationships between students' science performance and students' ICT availability, ICT use, and attitudes toward ICT were examined. The ICT Development Indexes (IDI) of 35 countries were used to investigate whether the relationships vary across countries. Two-level regression was employed for the analysis, taking into account plausible values and sample weights. The results indicated that there was a differential relationship among countries and regions for how much of the total variance was explained through ICT related factors. Controlling major student- and school-level variables, as IDI scores of countries increase, explained variances of science scores by ICT use, availability and attitude increase in South/ Latin America, whereas, for countries in Europe, the explained variances decrease. In Asia and Pacific, explained variances across countries were similar. Further implications are discussed emphasizing the importance of regions-based perspectives.