Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with metastasis significantly impacting patient outcomes. Alpha lipoic acid (ALA), a potent antioxidant, has shown promise in cancer treatment due to its ability to modulate key cellular pathways. The AMP-activated protein kinase (AMPK)-p53 axis plays a critical role in regulating cellular metabolism and tumor suppression, making it an attractive target for HCC therapy. This review aims to elucidate the potential of ALA as a modulator of the AMPK-p53 axis in HCC progression, focusing on its mechanisms and therapeutic potential in inhibiting metastasis. ALA exerts its anti-cancer effects through multiple mechanisms, including direct antioxidant activity, activation of AMPK, and modulation of p53 function. In HCC, ALA has been shown to inhibit cell proliferation, induce apoptosis, and suppress epithelial-mesenchymal transition, a key process in metastasis. ALA activates AMPK, which in turn inhibits mammalian target of rapamycin signaling and promotes p53 activation. This leads to cell cycle arrest, increased apoptosis, and reduced metastatic potential. In addition, ALA’s ability to modulate mitochondrial function and reduce oxidative stress further contributes to its anti-cancer properties. Preclinical studies have demonstrated ALA’s efficacy in reducing tumor growth and metastasis in HCC models, suggesting its potential as an adjunct therapy. The modulation of the AMPK-p53 axis by ALA represents a promising approach for HCC treatment, particularly in addressing metastasis. Further research is needed to optimize ALA’s therapeutic potential and evaluate its efficacy in combination with existing HCC therapies. This review highlights the importance of targeting metabolic and tumor suppressor pathways in developing novel strategies for HCC management.