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Self-efficacy is a predictor of future success, persistence, and interest in STEM. We documented students’ STEM interest and self-efficacy through their participation in a transdisciplinary curriculum that was implemented in two different settings—a university course taken by high school students, and a high school course. Students began with high STEM interest and self-efficacy and showed modest increases by the end of the program. Most of this increase was driven by students who participated in the high school course and who started with lower interest and self-efficacy. This study illustrates the importance of integrating transdisciplinary learning opportunities in high school settings, which serve a broader range of students and can make a greater impact on self-efficacy.