This research presents an innovative perspective on vocational education by merging the Instructional System Design (ISD) model with Innovation in Thailand Vocational Education and Training (InnoTVET) principles. Targeted at nursing students, the course aims to cultivate entrepreneurial skills while connecting vocational training with healthcare policy development. It aligns with global movements in Education for Sustainable Development (ESD), addressing the increasing demand for nurse entrepreneurs who can devise creative healthcare solutions within established policy frameworks. By employing mastery learning techniques alongside design thinking, the course effectively bridges theoretical concepts with practical applications. The mixed-methods study underlines relevant contribution in students’ entrepreneurial mindsets. Results from t-tests reveal the students’ ability to identify opportunities, engage in innovative thinking, and work within policy frameworks. Findings are supported by qualitative data, which demonstrate enhanced confidence, improved problem-solving capacities, and a deeper understanding of healthcare market dynamics. Although expert evaluation of student projects is scheduled for future iterations, the initial outcomes reinforce the course’s success. The course is structured into seven modules spanning 45 hours, featuring active learning components, five business-oriented assignments, and a final innovation project that integrates the curriculum’s core elements. This design ensures students develop both practical expertise and interdisciplinary insights critical to healthcare innovation. The integration of InnoTVET and ISD principles in nursing education sets a precedent for vocational education reform. This example of a successful nursepreneurship initiative provides a scalable model for enhancing vocational programs in diverse fields, fostering innovation and sustainability.