Background: Many countries worldwide implemented school closures to reduce COVID-19 transmission. By the new ‘homeschooling’ process, children could continue the regular school curriculum from the software-based system, which could alleviate parents' concerns about their children's educational attainment. However, parents still conduct more basic education and supervision, which may increase parental stress. Objective: This study aims to examine the interaction effect of homeschooling experience and pandemic-related worries on Chinese parents’ mental health. In addition, whether and how the relationship between homeschooling experience, pandemic-related worries and mental health could vary between women and men was examined. Method: This study recruited 746 Chinese parents with 10-18-year-old children during the COVID-19 pandemic. Data were analysed with multiple linear regression. Results: We found a higher level of job-related worries was associated with worse parental mental health (β= 3.593，P<.001). Additionally, the learning process was significantly positively correlated with parental mental health (acceptance of parental homework support β=1.748, P=.003; children’s completion of the studying task β=1.337, P=.018). Job-related worries significantly moderated the relationship between homeschooling and parental mental health (β=2.215, P=.026), while virus-related and life-related worries did not. Regarding gender differences, the interaction effects of job-related worries on the relationship between homeschooling and parental psychological symptoms were only significant among mothers (β=2.579, P=.020). Conclusion: Homeschooling is significantly associated with Chinese parents’ psychological symptoms. Parental worries are found to moderate the association between homeschooling and parental psychological symptoms. Moreover, job-related worries played a moderating role in the association between homeschooling and parental mental health. Thus, school intervention programs should also be implemented to help children adjust negative learning status in homeschooling.