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In June 2021, the COVID-19 spread again in the community, and residents had to face the impact of the outbreak again after 276 days, none of the local cases in Guangdong Province, China. The purpose of this study was to investigate the mechanisms underlying the relationship between intolerance of uncertainty (IU) and anxiety in college students in non-epidemic area during the periods of re-emergence of COVID-19. A survey was conducted among 86,767 college students in Guangdong Province, China from 10 to 18 June 2021, information on the Intolerance of Uncertainty Scale (IUS), General Anxiety Disorder-7 (GAD-7), Cognitive Emotion Regulation Questionnaire (CERQ) and Family APGAR Index were collected. Five moderation and mediation models were analyzed using latent moderated structural equations. The results showed that IU was positively related to anxiety (r = 0.42, p < 0.000). After controlling for age and gender, latent moderated structural equations indicated that catastrophizing mediated the relationship between IU and anxiety, and family function acted as a moderator in this relationship. Further analyses indicated that IU directly affected anxiety and had indirect effects on anxiety by catastrophizing. This relationship was weaker among college students who reported lower family function. This study provides practical implications for designing intervention strategies to reduce anxiety in college students when the epidemic re-emerges. • The relationship between IU and anxiety is discussed among college students when the COVID-19 spread again in the community. [ABSTRACT FROM AUTHOR]