Few studies have examined factors that might explain or affect the relationship between psychological flexibility and university students' COVID-19 burnout. The present study tested a moderated mediation model with perceived COVID-19 stress as the mediator and social support, a moderator, among 2377 Chinese college students. After controlling for gender, age, family location, and year of study (freshmen, sophomores, juniors, seniors), psychological flexibility was significantly associated with COVID-19 burnout, and this link was mediated by perceived COVID-19 stress. Social support buffered the adverse effects of perceived COVID-19 stress on psychological flexibility, as well as the correlation between perceived COVID-19 stress and burnout.