Background: Nurses proved unique experiences while caring for patients with several infectious diseases in isolation rooms. Purpose: This study aimed to explore the experiences of nurses caring for patients with infectious diseases in isolation rooms. Methodology: The study used a descriptive phenomenological approach using face to face in depth interviews from recruiting ten participants. The data were analyzed using Moustakas thematic analysis approach. Findings: The experiences of being a nurse caring for isolated patients were reflected in four major themes: (a) Risk perception and negative emotions, (b) Challenged with limited resources, (c) Isolation precautions interfere with optimum care, and (d) Knowledge and education. Discussion: Nurses encounter many challenges in caring for patients in isolation rooms, including fear and stress, inability to use precautions that increase disease transmission, and communication difficulties. Nurses should update their knowledge and competence regarding infection control precautions through a new standard of education and training.