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Abstract Metacognitive calibration—the capacity to accurately self-assess one’s performance—forms the basis for error detection and self-monitoring and is a potential catalyst for conceptual change. Limited brain imaging research on authentic learning tasks implicates the lateral prefrontal and anterior cingulate brain regions in expert scientific reasoning. This study aimed to determine how variation in undergraduate life sciences students’ metacognitive calibration relates to their brain activity when evaluating the accuracy of biological models. Fifty undergraduate students enrolled in an introductory life sciences course completed a biology model error detection task during fMRI. Students with higher metacognitive calibration recruited lateral prefrontal regions linked in prior research to expert STEM reasoning to a greater extent than those with lower metacognitive calibration. Findings suggest that metacognition relates to important individual differences in undergraduate students’ use of neural resources during an authentic educational task and underscore the importance of fostering metacognitive calibration in the classroom.