It is still unclear how CBD interferes with DNA replication and repair processes, but our study suggested a possible mechanism of action of CBD on HNSCC: CBD-induced DNA damage via the upregulation of MCM2, PARP1, or BRCA1 can be attributed to induce apoptosis and CBD also subsequent activation of KLF6, which might promote CDKN1A (p21) expression in cells. Here, CDKN1A is linked to head and neck squamous cell carcinoma.