Genomic instability is a prominent hallmark of cancer, however the mechanisms that drive and sustain this process remain elusive. Research demonstrates that numerous cancers with increased levels of genomic instability ectopically express meiosis-specific genes and undergo meiomitosis, the clash of mitotic and meiotic processes. These meiotic genes may represent novel therapeutic targets for the treatment of cancer. We studied the relationship between the expression of the meiosis protein HORMAD1 and genomic instability in squamous cell carcinomas (SCCs). First, we assessed markers of DNA damage and genomic instability following knockdown and overexpression of HORMAD1 in different cell lines representing SCCs and epithelial cancers. shRNA-mediated depletion of HORMAD1 expression resulted in increased genomic instability, DNA damage, increased sensitivity to etoposide, and decreased expression of DNA damage response/repair genes. Conversely, overexpression of HORMAD1 exhibited protective effects leading to decreased DNA damage, enhanced survival and decreased sensitivity to etoposide. Furthermore, we identified a meiotic molecular pathway that regulates HORMAD1 expression by targeting the upstream meiosis transcription factor STRA8. Our results highlight a specific relationship between HORMAD1 and genomic instability in SCCs, suggesting that selectively inhibiting HORMAD1, possibly, through STRA8 signaling, may provide a new paradigm of treatment options for HORMAD1-expressing SCCs.