Cell biology is the basic concept of biology that focuses on the Structure and functions of the Cell. It is therefore a pre requisite for understanding of Biology, a subject that is not only applicable in our daily lives but also key in the research and the production world. Despite the role of biology, failure rate in the subject remains high. The aim of this study was to determine the effect of 5E instructional model on academic achievement in cell biology concepts among students of biology in Vihiga County, Kenya. Effectiveness of the 5E model on improvement of various science outcome has been supported by research conducted in schools. Mixed method research design comprising of quasi-experimental design and focus-group interviews was used. A sample of 550 students and 12 teachers of biology was selected using multi-stage sampling procedure. Data was collected using two achievement tests and an interview schedule guide. The reliability of the research instruments was determined using Cronbach’s alpha coefficients while validity was established through consultation with research experts and practicing teachers. Data was analyzed using the independent sample t-test, at α = 0.05. The main finding was that the 5E instructional model greatly improved student’s academic achievement in cell biology concepts and additionally, it increased student’s interest in the subject. It was therefore concluded that the 5E instructional model improved students’ academic achievement in cell biology concepts. The results of this study may provide a basis for improving instruction in biology as well as in other subjects to realize improved achievement by the learners.