The relationship between Information and Communication Technology (ICT) and science performance has been the focus of much recent research, especially due to the prevalence of ICT in our digital society. However, the exploration of this relationship has yielded mixed results. Thus, the current study aims to uncover the learning processes that are linked to students’ science performance by investigating the effect of ICT variables on science for 15-year-old students in two countries with contrasting levels of technology implementation (Bulgaria n = 5,928 and Finland n = 5,882). The study analyzed PISA 2015 data using structural equation modeling to assess the impact of ICT use, availability, and comfort on students’ science scores, controlling for students’ socio-economic status. In both countries, results revealed that (1) ICT use and availability were associated with lower science scores and (2) students who were more comfortable with ICT performed better in science. This study can inform practical implementations of ICT in classrooms that consider the differential effect of ICT and it can advance theoretical knowledge around technology, learning, and cultural context.