Introduction Instruction and learning play an important role in the twenty-first century which has been named the knowledge society and knowledge economy. The present research seeks to design and implement a blended instructional model based on the theories of Reigeluth, Merrill, and Keller and investigate its effect on students’ learning in a biology course. Methods In this research, the pretest-posttest, quasi-experimental method with control was used. The population consisted of all second year high school students studying at Imam Khomeini high school in the 2013 - 2014 academic year. Using the random sampling method, the sample was selected and consisted of two classes, one of them as the control group and the other as the experimental group. Reliability of the research was calculated as 0.82 using the split-half method. Abundance, mean and standard deviation from descriptive statistics, and covariance methods were selected from inferential statistics, and SPSS version 20 was used to analyze data. Results The results revealed a meaningful and significant difference between the learning levels of the experimental group and the control group in a biology course (F1, 37 = 23.808; P < 0.01). The group which taught using the blended instructional design model based on the models of Reigeluth, Merrill, and Keller achieved a higher level of learning than the control group. Based on the results, it can be said that the research model has a good fit with real world data. Conclusions Use of the blended instructional design model based on Reigeluth, Merrill, and Keller’s models in a biology course was more effective than conventional methods. The findings indicate that the blended instructional design model is an effective and efficient method for teaching a biology course.