The integration of numerical simulations with Liver-on-a-Chip (LoC) technology offers an innovative approach for studying liver physiology and pathology, especially in the context of liver cancer. Numerical simulations facilitate the optimization of microfluidic devices’ design and deepen the understanding of fluid flow and mass transfer. However, despite significant advancements, challenges such as replicating the full complexity of the liver microenvironment and scaling up for high-throughput screening persist. This systematic review explores the current advancements in LoC devices, with a particular emphasis on their combined use of numerical simulations and experimental studies in liver cancer research. A comprehensive search across multiple databases, including ScienceDirect, Wiley Online Library, Scopus, Springer Link, Web of Science, and PubMed, was conducted to gather relevant literature. Our findings indicate that the combination of both techniques in this field is still rare, resulting in a final selection of 13 original research papers. This review underscores the importance of continued interdisciplinary research to refine these technologies and enhance their application in personalized medicine and cancer therapy. By consolidating existing studies, this review aims to highlight key advancements, identify current challenges, and propose future directions for this rapidly evolving field.