Hepatocellular carcinoma (HCC) is a highly malignant tumor with poor prognosis, and the tumor microenvironment (TME) remodeling plays a pivotal role in its progression. Cancer-associated fibroblasts (CAFs) and matrix metalloproteinases (MMPs) form a bidirectional regulatory axis (CAFs–MMPs axis) that serves as a core driver of TME imbalance in HCC. This review systematically elaborates on the origin and functional characteristics of CAFs, the classification and regulatory mechanisms of MMPs, and the bidirectional interaction logic between CAFs and MMPs (including cytokine signaling, mechanotransduction, and exosome-mediated communication). We further discuss the critical roles of this axis in shaping key malignant phenotypes of HCC, such as proliferation, invasion, metastasis, angiogenesis, immune evasion, and therapy resistance. Through cross-cancer comparison with pancreatic ductal adenocarcinoma, breast cancer, and colorectal cancer, we highlight the unique features of the CAFs–MMPs axis in HCC, which is closely linked to the liver’s chronic inflammatory and fibrotic microenvironment. Finally, we summarize the translational prospects of targeting this axis in clinical practice, including selective MMP inhibitors, CAF-targeted drug delivery systems, molecular imaging diagnosis, and combination strategies with immunotherapy. We also outline current challenges and future directions, aiming to provide a conceptual framework for microenvironment-oriented precision diagnosis and therapy in HCC.