Background: Various populations have experienced significant increases in depression and decreased quality of life (QOL) during the coronavirus disease 2019 (COVID-19) pandemic. This network analysis study was designed to elucidate interconnections between particular depressive symptoms and different aspects of QOL and identify the most clinically important symptoms in this network among adults in Wuhan China, the initial epicenter of the COVID-19 pandemic. Methods: This cross-sectional, convenience-sampling study (N = 2459) was conducted between May 25 to June 18, 2020, after the lockdown policy had been lifted in Wuhan. Depressive symptoms and QOL were measured with the Patient Health Questionnaire-9 (PHQ-9) and first two items of the World Health Organization Quality of Life Questionnaire - brief version (WHOQOL-BREF), respectively. A network structure was constructed from the extended Bayesian Information Criterion (EBIC) model. Network centrality strength and bridge strength were evaluated along with the stability of the derived network model. Results: Loss of energy (DEP-4) and Guilt feelings (DEP-6) were the two central symptoms with the highest strength as well as the two most prominent bridge symptoms connecting the clusters of depression and quality of life (QOL) in tandem with the two nodes from the QOL cluster. Network structure and bridge strengths remained stable after randomly dropping 75 % of the sample. Conclusion: Interventions targeting “Loss of energy” and “Guilt feelings” should be evaluated as strategies for reducing depressive symptoms and promoting improved QOL in COVID-19-affected populations.