This study investigated the effect of interactive computer simulation-supported inquiry on South African grade 8 learners' comprehension of atoms and molecular structures. Two sample groups of 34 learners per sample group were used, one acting as a control group who were exposed to a teacher-directed pedagogy while the experimental group used simulations in inquiry-based learning as an intervention to enhance their understanding of atomic and molecular structures. Data were collected by means of conceptual tests, a questionnaire survey, and individual interviews. A statistical analysis of quantitative data gleaned from the post-test showed that the learners in the experimental group performed better than the control group learners. This reflects that the interactive simulations using in an inquiry activity impacted more favorably on the conceptual understanding of learners compared to a teacher-directed approach. The results of the questionnaire survey indicated that learners in the experimental class had a positive experience of using the simulations. They recognized that the simulations enhanced their visualization of abstract concepts, and they reflected on their efficacy in manipulating the simulation.