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. Aim of the study: Investigate the effect of the entrepreneurial leadership intervention program on nurse interns’ work innovation and overall performance in the clinical setting. Setting: The study was carried out at Mansoura University Hospitals, Egypt. Subjects This study recruited nurse interns who worked 6 hrs. every shift, 36–40 hrs. per week; had at least 6 months of experience; and provided informed consent to participate in the program. The sample was calculated at 80% power, as it is a widely accepted standard in social and behavioral sciences to reduce the likelihood of type II error. Nurse interns were included in the study if they agreed to participate in the research and matched the eligibility requirements. Accordingly, 513 nursing interns served as the study group, and another 513 served as the control group. Study design: A two-arm, parallel, open-label randomized controlled trial. Tools for data collection: Entrepreneurship knowledge, entrepreneurial leadership behavior, the work innovation questionnaires, the observation checklist of nurses' performance, and the demographic information form. Results: 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. Conclusion: 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. Recommendation: Hospital administrators should incorporate structured entrepreneurial leadership programs into nurse internship and continuing education curricula to enhance nurses’ innovation, decision-making, and adaptability. Nurse managers should create an environment that supports creativity by allowing interns and staff to propose new ideas, implement process improvements, and engage in problem-solving discussions. Assign experienced nurses or entrepreneurial leaders as mentors to guide interns in developing leadership skills, resilience, and innovative thinking in clinical settings. Recognize and reward nurses who demonstrate entrepreneurial leadership, creativity, and problem-solving skills, reinforcing a culture of continuous improvement.