Abstract Virtual reality (VR) has been widely adopted in natural science education for learners to engage in inquiry-based learning in a safe and immersive environment. Also, the Predict-Observe-Explain-Evaluate (POEE) strategy is often used in inquiry-based activities to guide learners to understand and delve into their acquired knowledge during the inquiry process. However, the evaluation phase in conventional inquiry-based activities only provides feedback and solutions based on learners’ answers to the learning questions. Researchers have pointed out that without analysis and feedback on learners’ misconceptions, the learning effects of inquiry-based learning activities may be worse than expected. As a result, the present study proposed a Predict-Observe-Explain-Diagnose (POED)-based VR approach which could diagnose misconceptions and provide guidance. In VR learning activities, in addition to judging whether students’ answers are based on accurate reasons, it is helpful to further diagnose the possible misconceptions due to their wrong judgments so as to provide learning guidance. To explore the effectiveness of the proposed approach, the present study adopted a quasi-experimental design and recruited two classes of eighth graders as participants. One class was the experimental group adopting the POED-based VR approach, while the other class was the control group adopting the conventional POEE-based VR approach. The results showed that the experimental group had significantly better performance in learning achievement, problem-solving tendency, critical thinking tendency, and metacognition tendency than the control group. Besides, based on the behavioral analysis results, the POED-based VR approach could help students better understand their own misconceptions in learning, and then have more learning behaviors of reading supplementary materials, which was conducive to constructing accurate knowledge and improving learning performance.