Notoginsenoside Ft1 (NFt1) is a bioactive compound derived from Panax notoginseng, a traditional medicinal herb that exhibits various pharmacological properties, including anti-inflammatory and anticancer effects. However, its effects on hepatocellular carcinoma (HCC) remain poorly understood. This study sought to investigate the anticancer effects of NFt1 and uncover its fundamental mechanisms in HCC cells. NFt1 treatment inhibited cell proliferation and promoted apoptosis by enhancing cell death markers. Transcriptome profiling using RNA-sequencing revealed that NFt1 treatment downregulated the expression of oncogenes (e.g., FOS, BRAF, RARA, MYC, and JUND), while upregulating lysosomal cell death-related genes (e.g., CTSB, CTSD, LAMP1, LAMP2, and TPP1). These effects are associated with PI3K/AKT/mTOR inhibition and increased transcriptional activity of transcription factor EB (TFEB). NFt1 treatment induced autophagic traits by suppressing the PI3K/AKT/mTOR pathway, thereby enhancing TFEB transactivity. These findings demonstrated the therapeutic promise of NFt1 in the effective management of HCC.