Objective To evaluate the efficacy of generative AI (Gen-AI) in enhancing innovative entrepreneurship among nursing students in the teaching of Fundamentals of Nursing. Methods Cluster randomized sampling was employed to select second-year nursing students from a medical college in Guangxi and the students were divided into control group and experimental group. The control group received conventional teaching integrated with AI-related educational philosophy. The experimental group performed a teaching reform incorporating Gen-AI into traditional teaching, structuring the reform around three modules (concept inspiration, demand guidance, and improvement of existing tool), and four sessions (three class hours/120 minutes each) were dedicated to fostering innovation and entrepreneurship skills in the experimental group. The scores of innovation and entrepreneurship and course test before and after the intervention were compared between the two groups. Results Statistically significant differences were found between the two groups in overall innovative entrepreneurship, goal-setting, communication and collaboration, opportunity recognition, risk prevention, and resilience in adversity (P<0.05). However, no significant differences were observed in the scores of action planning or decisive decision-making (P>0.05). Additionally, no significant difference (P>0.05) was found in course performance between the two groups. Conclusion The integration of Gen-AI into the teaching of Fundamentals of Nursing demonstrates certain advantages in enhancing nursing students' innovative entrepreneurship. However, its implementation requires reinforced guidance, AI tool supervision, and rigorous evaluation to ensure teaching efficacy and safety.