The first purpose of this systematic review is to describe how empirical studies on the applications of the 5E instructional model are distributed according to certain variables. The second purpose is to determine how the 5E model has shown a trend in empirical studies in the transition from inquiry-based teaching to STEM education over the years within the scope of learning outcomes of the 5E model. A total of 74 empirical articles out of the 201 obtained from the initial search with the keyword '5E model' in the Web of Science (WoS) and Education Resources Information Center (ERIC) databases were subjected to descriptive and content analysis. The outstanding conclusion from the synthesis of these empirical studies in which the 5E model was implemented is that the 5E model, which has had a broad impact for a long time, focused on its effects on sublevel thinking levels of Bloom's taxonomy (knowledge, understand), and its effects on higher-order thinking levels, which have a crucial place in science education, are overshadowed. Based on these results, a 'skill-based STEM instructional model' with an activity set prepared by the model has been proposed in this study concerning 21-st century skills based on the 5E model.