Oncogenic types of human papillomaviruses (HPVs) are major human carcinogens. The viral E6/E7 oncogenes maintain the malignant growth of HPV‐positive cancer cells. Targeted E6/E7 inhibition results in efficient induction of cellular senescence, which could be exploited for therapeutic purposes. Here we show that viral E6/E7 expression is strongly downregulated by Metformin in HPV‐positive cervical cancer and head and neck cancer cells, both at the transcript and protein level. Metformin‐induced E6/E7 repression is glucose and PI3K‐dependent but—other than E6/E7 repression under hypoxia—AKT‐independent. Proteome analyses reveal that Metformin‐induced HPV oncogene repression is linked to the downregulation of cellular factors associated with E6/E7 expression in HPV‐positive cancer biopsies. Notably, despite efficient E6/E7 repression, Metformin induces only a reversible proliferative stop in HPV‐positive cancer cells and enables them to evade senescence. Metformin also efficiently blocks senescence induction in HPV‐positive cancer cells in response to targeted E6/E7 inhibition by RNA interference. Moreover, Metformin treatment enables HPV‐positive cancer cells to escape from chemotherapy‐induced senescence. These findings uncover profound effects of Metformin on the virus/host cell interactions and the phenotype of HPV‐positive cancer cells with implications for therapy‐induced senescence, for attempts to repurpose Metformin as an anticancer agent and for the development of E6/E7‐inhibitory therapeutic strategies. What's new? Inhibition of the viral E6/E7 oncogenes in human papillomavirus (HPV)‐positive cancer cells leads to cellular senescence, thus representing an attractive anti‐cancer therapeutic strategy. The antidiabetic drug Metformin has shown anti‐tumorigenic potential in HPV‐positive cancer cells, but whether Metformin affects the HPV oncogenes or the virus/host cell crosstalk remains unknown. Here, the authors show that Metformin efficiently inhibits viral E6/E7 expression. Metformin however protects HPV‐positive cancer cells against the pro‐senescent effects of E6/E7 inhibition and chemotherapy‐induced senescence. These results reveal profound effects of Metformin on the virus/host cell crosstalk in HPV‐positive cancer cells, with potential implications for their therapeutic susceptibility.