Learning science in the context of socio-scientific issues (SSI) is widely advocated for achieving the goal of scientific literacy that values using science in daily lives. While prior research suggests that SSI-based learning can promote students’ disciplinary knowledge and practices, less is known about students’ perceptions of SSI-based learning and how to support students in considering the epistemic aspects of SSI learning. In this study, we seek to address the research gap by examining students’ perceptions of their learning and how they appropriate the epistemic tools for systems thinking in an issue-based unit on the regulation of e-cigarettes. We used semi-structured interviews from 33 students in a midwestern U.S. high school as our primary data. The results suggest that students in general held positive attitudes towards SSI-based learning experiences and found SSI work to be 1) relevant, 2) interesting, 3) promoting agency, and 4) beneficial for their science learning. Also, we found that students differed in how they appropriated the epistemic tools for systems thinking ranging from lack of appropriation, to appropriating surface features, and to appropriating epistemic purposes. We conclude the paper by discussing how engaging students in meaningful learning activities may support students’ productive engagement in SSI learning.