Traditional disciplinary and interdisciplinary educational models often fall short in enabling students to transform problems and solutions for real-world needs. They restrict learners’ ability to deconstruct problems and innovate beyond their subject-based expertise, hindering the development of reflective practice in new and unknown situations across domains. This paper introduces the Challenge-Based Reflective Learning (CBRL) framework that emphasizes context-driven, challenge-based experiential learning process. It presents a novel approach to understanding cross-boundary interactions and learning, overcoming the limitations of traditional, discipline-bounded models involving inter- and trans-disciplinarity. CBRL cultivates reflective practice by nurturing domain-general competencies and domain-specific skills inherent in concrete human experiences. This paper translates reflective practice theories into actionable methods for higher education, demonstrating their application at the Iovine and Young Academy at the University of Southern California—a school that integrates technology, arts and design, and business and entrepreneurship through its reflective, challenge-driven learning approach. The case study outlines a four-year college curriculum that flexibly incorporates student interests and societal challenges across domains. This paper enhances the scholarship of reflective practice and transdisciplinary education and research, discussing the implications for cultivating new kinds of expertise needed in a postdigital era.