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Context: Phytochemicals have been promising candidates for cancer therapy, affecting various cancer initiation and progression stages. Kaempferide is a mono methoxy flavone that shows potent anticancer effects on multiple cancers both in vitro and in-vivo. Materials and Methods We evaluated the anticancer activity of Kaempferide against HCC using MTT assay. HepG2, Huh7 and N1S1 were used for preliminary in vitro studies. This is followed by an apoptosis analysis as assessed by Caspase 3 and Caspase 9 and Cell cycle analysis. The in-vivo effects of the compound were studied in N1S1 orthotopically injected SD rat model, where the animal was given Kaempferide (25mg/kg thrice a week) and Vehicle (Cremophor: Ethanol). The expression of caspase 9 and a critical tumor marker, TGF-β were assessed in both control and treatment tumor samples. Results Kaempferide-induced dose-dependent cytotoxicity in 3 HCC cell lines (HepG2 IC50 = 25µM, Huh7 IC50 = 18µM and N1S1 IC50 = 20 µM). Further, caspase-dependent apoptosis was also confirmed in vitro. Kaempferide exhibited S phase arrest in HepG2 cells as analysed by Cell cycle analysis. Kaempferide showed a significant reduction in tumor size and tumor volume in vivo. Histopathological evaluation by H &E staining confirmed that altered cells were significantly destroyed in the Kaempferide-treated animals, which correlates with tumor reduction compared to the vehicle-treated group. Caspase 9 levels were also found to be increased in the treatment group. TGF- β1, a crucial marker found in HCC that plays a major role in migration and proliferation of cells, was also downregulated in the treatment group (Control = 207.8 ± 22.9 pg/ml and Kaempferide-treated = 157.3 ± 13.8 pg/ml). Conclusion This study confirmed the potential of Kaempferide as a promising alternative against HCC.