Background <p>Leadership is essential for nursing to provide high-quality treatment, productive cooperation, and flexible responses to the always-developing healthcare environment. In nursing educational programs, entrepreneurial leadership places a strong emphasis on cultivating qualities that promote creative problem-solving and inventive thinking. These abilities can be employed in clinical settings to enhance patient care, leadership, innovation, and healthcare delivery. Social learning theory describes how these skills are acquired through learning, imitation, observation, and reinforcement.</p> Aim <p>to investigate the effect of the entrepreneurial leadership intervention program on nurse interns’ work innovation and overall performance in the clinical setting.</p> Methods <p>A two-arm, parallel, open-label randomized controlled trial was conducted at Mansoura University Hospital, Governorate, Egypt. 1026 nurse interns were included in the study. Random assignment was used to place nurse interns in either the study group (<i>n</i> = 513) or the control group (<i>n</i> = 513) by using the Entrepreneurship Knowledge Questionnaire, Entrepreneurial Leadership Behavior Questionnaire, the Work Innovation Questionnaire, Observation Checklist of Nurses Performance, and Demographic Information Form.</p> Result <p>There were statistically significant differences between the study and control groups in total entrepreneurial knowledge, total entrepreneurial behavior, total work innovation, total performance, and all their dimensions, particularly at the immediate post-intervention and follow-up stages, with p-values of 0.000. The study group demonstrated highly significant improvements in entrepreneurial knowledge, total entrepreneurial behavior, total work innovation, total performance, and all their dimensions, particularly at the immediate post-intervention and follow-up stages, with p-values of 0.000.</p> Conclusion <p>This study demonstrates the significant impact of a structured entrepreneurial educational program on enhancing entrepreneurial behavior, work innovation, and performance among nurse interns. The intervention led to substantial and sustained improvements in various professional competencies, with the study group consistently outperforming the control group. These results emphasize the importance of targeted leadership development programs in fostering critical skills and promoting long-term knowledge retention and practical application.</p> Clinical trial number <p>Not applicable.</p>