The concentration of oxygen in ambient air is 21.00%. It is one of the World Health Organization's lists of essential medications (WHO). However, a high oxygen concentration may alter the lung and result in oxygen poisoning. Surfactant production is impacted by high oxygen concentrations, which also cause alveoli to collapse. To prevent these hazards, the critical care nurse must be able to monitor oxygen administration and gradually reduce supplementary oxygen. One of the issues associated with inadequate understanding, attitude, and practice about oxygen therapy are still delivering appropriate oxygen administration, despite the fact that it is controllable. To provide high-quality treatment, nurses' skills, attitudes, and practices are crucial since they can significantly contribute to preventing respiratory issues caused by a lack of oxygen while hospitalized. Therefore, the purpose of this study was to evaluate nurses' practices, knowledge, and attitudes toward the administration of oxygen in 2022 at the University of Gondar Comprehensive Specialized Hospital in Northwest Ethiopia. Methods: Institutional based cross-sectional study was conducted among nurses working at the University of Gondar comprehensive specialized hospital from May 1 to August 5/2022. A simple random sampling method was used to select study participants and data was collected by presenting self-administrated questionnaires. The data were entered into Epi data version 4.6 and exported into SPSS version 22. Finally, summary statistics were used to describe the study population. Result: A total of 244 respondents have participated with a response rate of 100%. Of the total respondents, 55.3% of participants had good knowledge, 56.1% of study participants had favorable attitudes and 62.7% of participants scored good practice. Conclusion and Recommendation: More than half of the nurses were found to have adequate knowledge, attitude, and practice about oxygen administration. However, it is considerable and not enough. To enhance the knowledge, attitude, and practice of the nurses on oxygen administration more than the current status, the implementation of a comprehensive, systematic, and continuous educational program was recommended.