Previous research has illustrated the potential of flipped learning for assisting teachers in designing meaningful activities to promote students' higher order thinking skills; however, several previous studies have challenged the effects of flipped learning on students' learning. One of the key problems is the lack of an effective learning approach or tools to engage students in the flipped learning activity. In this study, a concept mapping-based Prediction-Observation-Explanation (POE) approach was incorporated into flipped learning (called CPOE-FL) to enhance students' scientific learning. Furthermore, a three-group experiment was conducted to assess the effects of the three flipped learning models, comprising the CPOE-FL approach, the POE-FL (incorporating POE into flipped learning) approach, and the C-FL (conventional flipped learning) approach. The experimental results displayed that the CPOE-FL approach can benefit the learning achievements and self-efficacy of the students with respectively lower prior knowledge and lower initial self-efficacy, in comparison with the POE-FL and C-FL approaches. Both the CPOE-FL and POE-FL approaches promoted the students' inner learning motivation, while the CPOE-FL approach enhanced the students' critical thinking. This proposed approach could provide a good reference for researchers or school teachers intending to implement POE-based flipped learning in the future.