Genomic homeostasis serves as the cornerstone for proper cranio-maxillofacial morphogenesis, orchestrating critical developmental processes through meticulous control of DNA replication fidelity, damage repair efficiency, and cell cycle progression. This comprehensive review delineates the intricate molecular networks that safeguard genomic integrity during cranio-maxillofacial development, with particular emphasis on four fundamental regulatory axes: (1) DNA damage response pathways, (2) cell cycle checkpoint mechanisms, (3) epigenetic modulation systems, and (4) chromatin structure organization. We systematically analyze how pathogenic perturbations in these mechanisms-manifesting in disorders such as Fanconi anemia (DNA repair deficiency), Li-Fraumeni syndrome (cell cycle dysregulation), Kabuki syndrome (epigenetic dysfunctions), and Pierre-Robin Sequence (three-dimensional genome structure disruption)-lead to characteristic craniofacial anomalies including microcephaly, cleft palate, and mandibular hypoplasia. The key mechanisms by which DNA damage repair, cell cycle regulation, epigenetic modifications and chromatin structure maintain genomic homeostasis were highlighted. The critical roles of disease-associated genes in maintaining genomic homeostasis during development also were highlighted. By integrating contemporary research findings with clinical observations, this work provides a mechanistic framework for understanding the etiopathogenesis of genomic instability-related craniofacial malformations, while identifying critical knowledge gaps that warrant future investigation to improve clinical outcomes for affected individuals.