Objective This article aims to sort out the problems in the whole process of biosafety management and provide reference for large-scale nucleic acid screening in the future. Methods We refer to the technical guidelines and the practice of other medical institutions, combined with our practical experience, summarized the problems and solutions needing attention in biosafety management in three aspects: nucleic acid sampling place, personal protection and the process from sample collection to detection. The sampling team was strictly required to implement the standard requirements, so as to complete the screening task with quality and quantity. Results A total of 361 841 samples were collected during SARS-CoV-2 nucleic acid screening. No samples were contaminated or lost, and no biosafety accident occurred. The sampling task were successfully completed. Conclusion Large-scale SARS-CoV-2 nucleic acid screening is an important method to find out the source of the epidemic and curb the spread of the SARS-CoV-2 pandemic. In order to ensure the biosafety of the whole process, sufficient preparations should be made and biosafety measures should be strictly implemented.