Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a serious threat to international public health. The SARS-COV-2 gene continues to mutate in COVID-19 outbreaks. Mutation mainly manifests in 3 forms: point mutation, gene recombination and epigenetic modification. Viral mutations are driven by multiple factors, with mutation rates modulated at 3 levels, the nature of virus, host-virus interactions and natural selection. Therefore, it is particularly important to strengthen the monitoring of the global novel coronavirus genome and the protection of immunosuppressed populations. In the early stage of virus evolution, the mutant strains exhibit greater transmissibility and less virulence than the wild-type strain, although 5 variants of concern (VOCs) showed different stability, transmission capacity, adaptability and pathogenicity. So physical interventions need to be further strengthened. As herd immunity is established, novel mutant strains tend to mutate against vaccines and antibodies. In that case, VOCs, especially the prevailing Omicron variant, bring challenges to the prevention and control of COVID-19 worldwide. The existing and potential prevention, diagnosis and treatment approaches for COVID-19 were summarized. In the vaccination part, the protective efficacy of COVID-19 vaccine against VOCs and the factors influencing the efficacy of COVID-19 vaccine were analyzed. In the detection part, the detection methods based on nucleic acid, antigen and antibody were summarized in order to satisfy the requirements for point-of-care testing and timely recognition of novel variants. And in the treatment part, the potential therapeutic drugs and targets of SARS-CoV-2 were summarized. Drug targets are generally divided into extracellular targets and intracellular targets. In general, this review proposes possible countermeasures by analyzing the impact of mutations on global epidemic prevention and control, hoping to provide theoretical basis for possible large-scale epidemic prevention and control in the future.