This article aims to identify the challenges and opportunities in cross-program problem-based learning (PBL) in higher education, based on an Industry 4.0 case with undergraduate and graduate students studying for engineering degrees. The method for this research comprised a cross-program course structured to bring together undergraduate and graduate students using a PBL approach. Five Industry 4.0-related projects were developed in collaboration with four multinational companies. The authors present the results of the projects and feedback from students, professors and industry partners. The results and feedback led to empirical findings on the challenges and opportunities of cross-program PBL in higher education. The findings contribute to the design and implementation of teaching and learning practices and educational policies at undergraduate and graduate levels. In the approach adopted, the undergraduate students acquired hands-on experience while the graduate students had the opportunity to supervise applied research and practice. The study highlights practices that can help to better prepare future industry professionals.