Objective To deeply understand and explore the real experience of ICU nurses caring for patients developing infections with multi-drug resistant organisms (MDRO) and to provide empirical support for clinical optimization of nursing strategy and improvement of MDRO infection control program. Methods Sixteen ICU nurses from Nanning, Liuzhou, Guilin and Baise in Guangxi Zhuang Autonomous Region were selected by purposive sampling method from October to November 2023 for semi-structured in-depth interviews. Colaizzi 7-step analysis method was used to analyze, summarize and refine the themes of interview content. Results A total of 4 themes and 14 sub-themes were extracted:complex emotional experience (confidence and crisis, responsibility and guilt, emotion and powerlessness, fear and worry, fatigue and exhaustion, self-worth and professional identity challenges); multiple needs (scheduling and human resources management, learning and training, communication and cooperation, environment and equipment); continuous deepening of professional cognition (the sense of professional mission is strengthened, and the sense of sensory control work is focused on details); continuous reflection on self-growth (maintaining self-adjustment of the spirit of prudence and psychology). Conclusion ICU nurses have complex multi-dimensional experience and multi-faceted needs when caring for patients with MDRO infection. Managers should take targeted measures to improve nurses′ psychological capital, meet their professional needs, promote their professional growth and self-improvement, and then continuously improve the level of nursing services.