Weaning from mechanical ventilation defined as the process of brusquely or slowly discontinues ventilator support after a patient is able to sustain spontaneous breathing. The success of weaning depends on the resolution of the conditions that have caused the patient to be mechanically ventilated, daily ventilator performance assessment for weaning the patient, the patient readiness and effective application of weaning protocol and the weaning process. Objective: - The aim of this study was to assess knowledge, practice and associated factor regarding weaning patients from mechanical ventilation among nurses working in adult ICU of selected governmental hospitals Addis Ababa, Ethiopia, 2020 GC. Methodology: -Descriptive cross-sectional study design was conducted to determine adult ICU nurses' knowledge, practice and associated factors on weaning patient from mechanical ventilation in selected government hospitals. A total of 156 nurses were recruited by convenience sampling method. The data were collected by using semi structured self-administered questionnaires. SPSS version 25 was used for data entry and analyses. Descriptive statistics, bivariate and multivariate logistic regression were used to analyze the data. Result: - The finding revealed that, 89 (51.9%) of respondent had poor knowledge and 88 (56.41%) of them had poor practice toward weaning patient from mechanical ventilation. On bivariate logistic regression P<0.05, factors that had significant association on knowledge was an ICU work experience and training on weaning guideline. Also ICU work experience, educational status and availability of weaning protocol had a significant association with P <0.05 on the practice of ICU nurses. Conclusion and recommendation: The participants of this study had poor knowledge and practice. Work experience, weaning protocol training and availability of protocol had statistically significant with practice of ICU nurses. Therefore, to improve the levels of knowledge and practice, the investigator recommends continues on job training, preparation of protocols and supportive supervision is important.