Antibiotic resistance (ABR) is a significant contemporary socio-scientific issue. To engage in informed reasoning about ABR, students need to understand natural selection. A secondary science unit was designed and implemented, combining an issues-based approach and model-based reasoning, to teach students about natural selection and ABR. This sequential explanatory mixed methods study explored students’ explanations of natural selection. Students created model-based explanations (MBEs) about ABR and verbally explained generalised natural selection during semi-structured interviews. Students’ MBEs significantly increased in natural selection content, and misconceptions about natural selection and ABR significantly decreased after the unit. However, students’ explanations of generalised natural selection differed from ABR explanations. Students struggled to include mutation as the cause of initial variation when explaining generalised natural selection, whereas students included mutation when explaining ABR but often did so after selection pressure. Qualitative analysis indicated students correctly explained ABR or correctly explained generalised natural selection, but none correctly explained both. Students who did understand ABR struggled to apply their understanding to a context other than ABR. This study demonstrates contextual differences in students’ natural selection ideas and provides implications for natural selection instruction. While ABR is a compelling issue to contextualise natural selection instruction, it may be problematic.