IntroductionSingle-cell RNA sequencing (scRNA-seq) is a powerful tool for understanding cellular heterogeneity and identifying cell types in virus-related research. However, direct identification of SARS-CoV-2-infected cells at the single-cell level remains challenging, hindering the understanding of viral pathogenesis and the development of effective treatments.MethodsIn this study, we propose a deep learning framework, the single-cell virus detection network (scVDN), to predict the infection status of single cells. The scVDN is trained on scRNA-seq data from multiple nasal swab samples obtained from several contributors with varying cell types. To objectively evaluate scVDN’s performance, we establish a model evaluation framework suitable for real experimental data.Results and DiscussionOur results demonstrate that scVDN outperforms four state-of-the-art machine learning models in identifying SARS-CoV-2-infected cells, even with extremely imbalanced labels in real data. Specifically, scVDN achieves a perfect AUC score of 1 in four cell types. Our findings have important implications for advancing virus research and improving public health by enabling the identification of virus-infected cells at the single-cell level, which is critical for diagnosing and treating viral infections. The scVDN framework can be applied to other single-cell virus-related studies, and we make all source code and datasets publicly available on GitHub at https://github.com/studentiz/scvdn.