Information and communication technology (ICT) is key to educational development. This study explores the mechanism influencing the use of ICT on students' science literacy. We utilized two-level hierarchical linear models and structural equation models to analyze data collected from the 2015 Program for International Student Assessment (PISA) in China. Results indicate that student-level and school-level ICT factors, in particular ICT interest, autonomy in using ICT, and ICT availability at school positively impact the development of students' science literacy. Further, we found some notable interactions between school-level factors and student-level ICT variables. Moreover, there are structural relationships among ICT availability, ICT emotional perception, ICT learning usage behaviors, science self-efficacy, and science literacy. We also found that teacher-delivered science instruction has a negative moderating effect on ICT learning usage and science self-efficacy. These findings have important implications of how to integrate ICT in future science teaching practices.