This study examined students' genetics learning in a game-based environment by exploring the connections between the expectancy-value theory of achievement motivation and flow theory. A total of 394 secondary school students were recruited and learned genetics concepts through interacting with a game-based learning environment. We measured their science self-efficacy, science outcome-expectancy beliefs, flow experience, feelings of frustration, and conceptual understanding before and after playing the game, as well as their game satisfaction. Mixed-model ANOVA, correlation tests, and path analysis were run to answer our research questions. Based on the results, we found that the game had a significant impact on students' conceptual understanding of genetics. We also found an acceptable statistical model of the integration between the two theories. Flow experience and in-game performance significantly impacted students' posttest scores. Moreover, science outcome-expectancy belief was found to be a significant predictor of students' flow experiences. In contrast, science self-efficacy and pretest scores were found to be the most significant factors influencing the feeling of frustration during the game. The results have practical implications with regard to the positive role that an adaptive game-based genetics learning environment might play in the science classroom. Findings also underscore the role the teacher should play in establishing productive outcome expectations for students prior to and during gameplay.