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Objective: We aimed to assess which metabolic pathways would be implicated in the phenotypic changes of the epithelial lining of odontogenic keratocyst after marsupialization, comparing pre‐ and post‐marsupialized lesions with adjacent oral mucosa. Materials and Methods: Eighteen formalin‐fixed and paraffin‐embedded tissues from six subjects were divided into three paired groups: odontogenic keratocyst pre‐ (n = 6) and post‐marsupialization (n = 6), and adjacent oral mucosa (n = 6). The metabolic pathways found in these groups were obtained by high‐performance liquid chromatography‐mass spectrometry‐based untargeted metabolomics performed. Results: Through putative metabolite annotation followed by pathway enrichment and predictive analysis with automated algorithms (Mummichog and Gene Set Enrichment Analysis), we found differences in many cellular processes that may be involved in inflammation, oxidative stress response, keratinocyte‐basal membrane attachment, differentiation, and proliferation functions, all relevant to odontogenic keratocyst pathobiology and the phenotype acquired after marsupialization. Conclusion: Our study was able to identify several metabolic pathways potentially involved in the metaplastic changes induced by marsupialization of odontogenic keratocysts. An improved comprehension of this process could pave the way for the development of targeted therapies. [ABSTRACT FROM AUTHOR]