Objective: To investigate and compare the changes and associated factors of knowledge, attitude and practice of college students in Shanghai between the early 2020 and the end of 2021 stages of the COVID 19 epidemic and analyze the influencing factors, so as to provide reference for epidemic prevention and health education of college students. Methods: A retrospective cross sectional survey was conducted among 913 college students in 12 colleges and universities in Shanghai in 2021 from November to December with a self designed questionnaire by multi stage stratified cluster sampling, so as to investigate the changes of college students health literacy related to COVID 19 and the changes of knowledge, attitude and practice between the early 2020 and the end of 2021 stages of the COVID 19 epidemic. Results: In the early stage of the epidemic, the average score of understanding of epidemic prevention and control policies was(2.93±0.94), information judgment was(3.10±0.89), satisfaction degree was(4.11± 1.09 ), cooperation degree was(4.31±0.96), communication intention was (3.91±1.15). By the end of 2021, the understanding of prevention and control policies was (2.95±0.98); Information judgment was (3.77±0.94), satisfaction degree was (4.22±1.10), cooperation degree was (4.36±0.99), communication intention was (3.97±1.20), there were significant changes at different stages ( P <0.01). The results of binary Logistic regression showed that majors of social sciences (OR=0.62), majors of natural sciences ( OR =0.62), self rated good health ( OR =0.62) and self rated relatively good health ( OR =0.28) were negatively correlated with college students cognition and attitude changes to the COVID 19 epidemic ( P <0.05), while the choice of "relatively consistent"( OR =3.31) in "change in health behavior according to reasonable health information" was positively correlated with knowledge and attitude changes ( P <0.05). Shanghai college students health literacy about epidemic prevention was generally high. 79.4% of them had a "relatively high" score (>80), and 82.6% of the students rated themselves "very well" and "relatively well" knew epidemic prevention. Conclusion Relatively high level of health literacy on epidemic prevention is observed among college students in Shanghai. There had been significant changes in their knowledge, attitude, and practice of the epidemic since the early stage. It is necessary to carry out more accurate and effective health education and dissemination according to different characteristics, so as to build the prevention and control barrier of epidemic among college students.