Lysophosphatidic acid (LPA), a key bioactive lipid, modulates cellular functions through interactions with LPA receptors (LPAR1-6) of the G protein-coupled receptor (GPCR) family, participating in both physiological and pathological processes. While LPA/LPAR signaling typically promotes cancer progression by regulating angiogenesis and cancer cell metastasis, our study unexpectedly reveals that LPA exhibits an inhibitory effect on cellular activity in hepatocellular carcinoma (HCC). We further investigate the specific receptor subtypes mediating these effects and elucidate the underlying mechanisms at the cellular, tissue, and organismal levels. Pharmacological studies demonstrated that LPA predominantly inhibits HCC progression through activation of LPAR6. Mechanistically, LPA/LPAR6 activation suppresses HCC proliferation, migration, and epithelial-mesenchymal transition (EMT). In vivo, LPAR6 overexpression in a nude mouse xenograft model significantly reduced tumor growth rate and volume, accompanied by decreased Ki-67 expression in tumor tissues, as shown by immunohistochemical analysis. Transcriptomic analysis combined with Western blot experiments demonstrated that LPA/LPAR6 inhibits YAP/TAZ nuclear translocation, thereby suppressing HCC cell proliferation and migration. In conclusion, these findings suggest that enhancing LPAR6 expression or developing LPAR6 agonists may offer a promising therapeutic strategy for adjuvant cancer treatment.