The development of students' interest in school science activities, their understanding of central chemical concepts, and the interplay between both constructs across Grades 5-11 were analyzed in a cross-sectional paper-and-pencil study (N = 2,510, mean age 11-17 years). Previous empirical findings indicate that students' knowledge increases over the time of secondary school while students' interest, especially in natural science subjects, tends to decrease. Concomitantly, there is evidence for an increase in the positive coupling between interest and knowledge across time. However, previous studies mainly rely on rather global measures, for example, school grades or general subject-related interest, and focus on science as an integrated subject instead of specific disciplines, for example, chemistry. For this article, more proximal and differentiated measures for students' understanding of three chemical concepts (Chemical Reaction, Energy, Matter) and interest in seven dimensions of school science activities according to the RIASEC + N model (Realistic, Investigative, Artistic, Social, Enterprising, Conventional, and Networking; cf. Dierks, Höffler, & Parchmann, 2014) were applied. The results are in line with previous research indicating a general increase in conceptual understanding and a decline in students' interest for all school science activities. However, the interplay between conceptual understanding and interest differs across the seven dimensions. Interest in activities which are likely to promote cognitive activation (investigative, networking) or involving the communication of knowledge (social, enterprising, and networking) are increasingly connected to conceptual understanding, especially in upper secondary grades. Interest in guided hands-on activities (realistic) which are typical in secondary science teaching, however, shows only small positive correlations to students' conceptual understanding across all grades. Hence, in upper-secondary school, investigative, social, enterprising, and networking activities seem to provide opportunities to benefit most from the interrelation between students' interests and their understanding.