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According to self-determination theory, autonomy predicts learners’ interest, engagement, and learning. In this study, we sought to understand the neural processes that mediate the relations between autonomy, interest, engagement, and learning. We asked 24 participants to see a national flag, to rate their autonomy during that learning episode, and then to learn new information about that national flag. Self-report data showed that autonomy predicted interest and learning. fMRI data showed that late-trial dorsolateral prefrontal cortex (DLPFC) activity, correlated with early-trial anterior insular cortex (AIC) activity, predicted learning the new information about the corresponding national flag. Results confirmed that autonomy predicts learning through the neural mediations of AIC activity (related to autonomy), DLPFC activity (related to cognitive engagement), and their interactions.