Concept comprehension is an important foundation for more complex thoughts. To enhance concept comprehension, teachers of traditional classrooms have been using instructional strategies and specific course designs, which have been proven effective. It initiates a hypothesis that integrating instructional strategies in the course designs of an e-learning system would improve the effectiveness of concept comprehension. The purpose of this study is to propose a framework that integrates the learning cycle with variation theory in the course design of a web-based e-learning system to prove the hypothesis. A pretest and posttest quasi-experimental design is employed to test whether the framework is feasible. Two types of web-based courses are designed for the experiments: a course designed according to a science textbook and another course designed using the framework. The participants in this study were 120 fifth-grade students in Taiwan. The results of the experiments show that the average scores of the experimental group, using the course designed with the framework, are significantly higher than that of the control group, using the course designed without any instructional strategy, on comprehension of course concepts. This confirms that the coherent, explicit and systematic framework is feasible for designing web-based e-learning courses for effectively enhancing concept comprehension as well as the evidence to prove the hypothesis.