Computer simulations hold great potential for enhancing chemistry instruction. However, effectively integrating simulations in instruction depends in part on teachers’ pedagogical reasoning about simulation affordances and instructional decisions within specific classroom contexts. The objective of this study was to investigate how two chemistry teachers evaluated an interactive simulation and determined pedagogical strategies for integrating the simulation into classroom instruction. Based on the TPACK framework, authors adopted a comparative case study approach to interpret qualitative data from three sources: screen-capture videos, interviews, and instructional plans. Results showed that pedagogical reasoning and decisions of the two participants reflected different TPACK components. One teacher mainly utilized TCK and evaluated the simulation from a designer’s perspective while the other teacher leveraged TPACK and reasoned from a learner’s perspective. The two teachers’ reasoning processes further shaped their decisions about how to integrate the simulation in instruction, which displayed TPK and TPACK. One teacher intended to provide students with careful guidance by constraining system variables while the other favored more open-ended exploration. Results suggest that teacher knowledge, pedagogical reasoning, and decisions are closely intertwined, which provide implications for future research.