Cholangiocarcinoma (CCA) presents a significant therapeutic challenge due to its poor prognosis and the complex interplay of metabolic pathways in its development. This study aims to elucidate the genetic, biochemical, and metabolic factors contributing to CCA’s pathogenesis to inform more targeted and effective treatment strategies. A comprehensive review of the current literature was conducted, focusing on the role of genetic variations and metabolic disruptions in CCA. Key pathways such as PI3K/AKT/mTOR, FGFR, and IDH were examined, along with their impacts on carbohydrate, lipid, nucleic acid, and amino acid metabolism. The findings indicate that the liver’s vital role in regulating these metabolic processes means that disruptions can profoundly influence disease progression. Genetic variations were found to significantly alter both metabolic and signaling pathways, contributing to the aggressive nature of CCA. Understanding the complexities of genetic and metabolic interplay in CCA is essential for developing more targeted and effective treatment strategies. This review highlights the importance of these pathways in the pathogenesis of CCA and suggests potential therapeutic targets for future research.