Objectives This study investigated the efficacy of flipped approach on the nurses’ knowledge and motivation regarding critical respiratory care during the COVID-19 pandemic. Results This pretest-posttest quasi-experimental study was performed in a hospital affiliated with Shiraz University of Medical Sciences during March-December 2021. One hundred and twenty eligible nurses selected by convenience sampling underwent a seven-day flipped approach respiratory intensive care training. The nurses’ motivation and knowledge were evaluated using the Students’ Motivation Towards Science Learning (SMTSL) and a 20-researcher-made four-option questionnaire before and two weeks after the intervention, for knowledge assessment respectively. The nurses’ knowledge and learning motivation were significantly higher after the intervention (P < 0.001). The flipped approach can improve learning motivation and nurses’ knowledge of critical respiratory care.