Background <p>Quinoa is a new type of grain crop that has become popular in recent years. It is resistant to drought, and saline-alkali conditions. However, global warming has led to increased rainfall, making it susceptible to waterlogging stress during the growing season. The filling period is a critical period for plant growth and development, but there have been few reports on quinoa response under stress condition during the filling period in recent years.</p> Methods <p>Based on transcriptome data, combined with morphological and physiological indicators and significant metabolites under waterlogging stress, WGCNA (Weighted gene co-expression network analysis) was used to construct a co-expression network associated with it, mine relevant hub genes, and perform overexpression and functional verification of one of the genes.</p> Results <p>We used the WGCNA method to identify 11 hub genes that respond to waterlogging stress, six of which are transcription factors encoded by the <i>AP2/ERF</i>, <i>NAC</i>, and <i>C3H</i> gene families. One of the hub genes, <i>LOC110688032</i>, was overexpressed in <i>Arabidopsis</i>, and its T2 generation seedlings were phenotyped and functionally validated. It was found that overexpression of the <i>LOC110688032</i> gene in <i>Arabidopsis</i> enhanced the tolerance to waterlogging of the transgenic.</p> Conclusions <p>The results of this study provide valuable insights for quinoa resistance research and lay a solid foundation for the future development of superior quinoa varieties with good tolerance to waterlogging.</p>