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This study aimed to examine the role played by the physical literacy and mindfulness in the health-related quality of life (QoL) of college students. In early 2022, 24,236 college students from three universities in southern China were recruited in the study. R software and the lavvan package was utilized to build the structural equation model. The measurement model was composed of three latent factors (physical literacy, mindfulness, and quality of life) and 16 observed variables in total. The results of the measurement model indicated goodness fit with p > .05 in Chi-square result, and GFI = .92. In addition, the comparative fit index (.92), Tucker-Lewis index (.91), root-mean-square error of approximation (.07), and root of mean square residual (.11) were in accord with the cutoff model-fit criteria. The results confirm that physical literacy and mindfulness can play a significant and positive role in the structural equation model of quality of life. In addition, this study provides initial evidence that mindfulness and physical literacy could potentially buffer declines in student QoL during the COVID-19 pandemic. Moreover, this study is the first to develop a structural equation model of QoL with multiple indicators, making it a strong addition to existing research on QoL during a pandemic., (© 2024. The Author(s).)