Background End-of-life care can be a difficult and challenging process for critical care nurses in intensive care units (ICUs) due to the care plan shifts from providing life-sustaining measures to end-of-life care. The aims of this study were to assess critical care nurses' perceived knowledge and attitudes toward end-of-life care, as well as their perspectives on promoting advance directives and the associated factors. Methods A cross-sectional study was undertaken in an acute major metropolitan medical center in northern Taiwan between February and March 2020, and 250 critical care nurses were invited to participate in the study. Data on demographics, self-perceived knowledge of end-of-life care, attitudes toward end-of-life care, and perspectives of promoting advance directives were collected. A multiple linear regression model with stepwise selection was used to identify factors associated with their perspectives of promoting advance directives. Results The law related to end-of-life care was rated as the least familiar part of the self-perceived end-of-life care knowledge, while ‘I have sufficient knowledge to care for patients who have accepted end-of-life care’ was the lowest level of agreement in attitude scores among critical care nurses. Increased levels of perceived knowledge (β = 0.134; p = 0.045) and attitudes (β = 0.423; p < 0.001) toward end-of-life care were associated with the perspectives of promoting advance directives. Nurses who worked in cardiac (β = -0.234; p < 0.001) and respiratory ICUs (β = -0.135; p = 0.024) had less motivation to promote advance directives (F = 16.943; p < 0.001). Conclusion Given their important contributions to ICU care services, appropriate and meaningful support is required to optimize critical care nurses' involvement in end-of-life care. This study demonstrated a significant impact on perspectives of promoting advance directives of critical care nurse participants. Findings from this study can inform the design of effective nurse support programs to enhance the promotion of advance directives in intensive care settings.