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This study investigated the effects of teaching concepts of motion and force using the predict-observe-explain (POE) inquiry strategy to enhance a science game. Two groups of seventh-grade students played the same game, but the experimental group additionally followed a POE inquiry guide in the gameplay. Students’ in-game performance and inquiry behaviors were examined along with their conceptual understanding of the target physics concepts. The findings suggested that the experimental group significantly outperformed the other group in both conceptual understanding and game scores. The analysis of the two groups’ inquiry behavioral data revealed different learning pathways, which shed light on how the inquiry guide helped students in GBL. The article ends with practical implications for implementing game-based science learning.