The experiment was designed to explore the effects of domain knowledge, instructional manipulation, and the interaction between them on creative idea generation. Three groups of participants who respectively possessed the domain knowledge of biology, sports, or neither were asked to finish two tasks: imagining an extraterrestrial animal and creating a new sport. Participants in each group were randomly assigned to one of three instructions, in order to encourage them to perform the tasks using a specific instance strategy (relying on specific instances), an abstract strategy (relying on abstract principles), or their habitual ways. Based on an analysis of the participants' verbal reports and their creations, the results suggested that domain knowledge enhanced the tendency to use the abstract strategy, and improved the originality and practicality of the generated ideas. Instructions also influenced the strategy participants used in creative idea generation. The instruction to use abstract principles brought forth the most original creations. Moreover, there was an interaction between domain knowledge and instructions. Encouraging participants to use the specific instance strategy blocked the knowledgeable people from developing novel ideas. Other factors, such as age, grade and gender, were found to be unrelated to either the originality or the practicality of the creations. The implications of the results were discussed in detail.