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Abstract Background Before the pandemic, research had already established the potential impact of perceived life stress and social support on the mental health status of Chinese students. However, in the Post-COVID Era, the specific mechanisms linking these variables and the distinct role of online social support remain relatively unexplored. Methods After the cessation of China’s dynamic zeroing policy, a total of 1180 university students from Northwestern China participated in this study by completing a demographic questionnaire, as well as self-report measures assessing mental health, perceived life stress, and online social support. Results Approximately 25% of students exhibited psychological symptoms. When examining different categories of perceived life stress, males reported experiencing a significantly greater impact in terms of punishment and interpersonal relationships compared to females. Females experienced significantly higher levels of learning pressure compared to males. Specific types of perceived life stress were found to be significant predictors of students’ mental health status. Moreover, online social support was identified as a significant moderator in the relationship between all types of perceived life stress and mental health, irrespective of gender. Conclusion Our study findings unveiled two significant aspects: Firstly, the impact of perceived life stress on the mental health of students was identified as a risk factor. Secondly, the role of online social support emerged as a protective factor, particularly in the post-pandemic context. Additionally, gender-specific patterns were observed in these relationships.