The Humanitarian Engineering and Social Entrepreneurship (HESE) Program engages students and faculty across Penn State in the rigorous research, design, field-testing, and launch of technology-based social enterprises that address global development challenges. HESE ventures are embedded in a series of five courses that integrate learning, research, and entrepreneurial engagement. The goal is to educate globally-engaged problem solvers who can create sustainable and scalable value for partnering communities, while simultaneously generating and disseminating new knowledge and lessons learned. This article describes the genesis, foundational philosophies, programmatic learning outcomes, and course mechanics of the HESE Program. The eplum model of student engagement, which embeds HESE sub-projects into regular credit classes and provides rigorous yet non-travel-based experiences to a cross section of students, is discussed. A mixed methods approach is utilized to examine the effectiveness and impact of the eplum curricular model on student learning, specifically in the areas of global awareness, multidisciplinary teamwork, and entrepreneurship education. The entrepreneurial and research outcomes of the program are summarized with a culminating discussion on the emergence of an educational and entrepreneurial ecosystem that has proved pivotal to actualize the ventures and achieve sustainable impact.