The coronavirus disease 2019 (COVID-19) has been spreading rapidly as a pandemic and posed numerous challenges to healthcare workers (HCWs), especially nurses. This study aimed to investigate the occupational challenges experienced by intensive care unit (ICU) nurses in caring for patients with COVID-19. This qualitative study was conducted using a conventional content analysis method in September and October 2020. The study environment was the ICU wards dedicated to the patients of COVID-19 in a large hospital in east of Iran. The participants were selected by purposeful sampling method, and data were collected using semi-structured interviews with 17 nurses working in the COVID-19 ICUs. Data analysis was done with MAXQDA 2020. The data analysis led to the extraction of 6 main categories and 17 sub-categories. The main challenges included "payment system", "human resource management", "consumable resource supply", "psychological and ethical distress", "personal or family problems", and "staff motivation and welfare issues". Considering the key and important role of nurses in the healthcare system, particularly during the COVID-19 pandemic, it is necessary to increase their motivation by applying a fair and non-discriminatory payment system and paying special attention to psychological issues. Also, managerial support and provision of required facilities and manpower have a significant impact on reducing their occupational challenges in caring for patients with COVID-19.