Background: Nurses play a vital role in caring for patients receiving extracorporeal membrane oxygenation (ECMO) for severe respiratory or cardiac failure. However, this area of nursing practice presents unique challenges. Accordingly, understanding these challenges is essential to improve patient care and support nurses' well-being. Aims: This study aimed to investigate and identify challenges nurses face in providing care to patients on ECMO. Method: A quantitative cross-sectional study of eligible nurses was conducted at King Faisal Specialist Hospital and Research Center in Riyadh City (KFSH&RC-R). A survey instrument developed by the principal investigators was used to collect data. A panel of ECMO specialists and clinical experts validated the survey content. Results: A total of 66 nurses (75.8% females, 60.6% aged 25–34 years, 33.3% with 1–5 years of nursing experience, and 87.9% holding a bachelor's degree in nursing) participated in the study. The identified challenges were managing complex equipment, maintaining stability, coordinating with multidisciplinary teams, addressing ethical dilemmas, managing high acuity, coping with stress, and prioritizing self-care. Conclusions: These findings highlight the multifaceted challenges nurses face in caring for patients on ECMO, which influence their well-being, job satisfaction, and the quality of care provided. Thus, interventional strategies to address these issues in this specialized area are urgently required.