Lactobacillus plantarum KFY02 (LP-KFY02) was isolated from naturally fermented yoghurt in Xinjiang. We previously demonstrated that LP-KFY02 has good biological activity in vitro. In this study, LP-KFY02 was used to ferment grape skin, and the LP-KFY02 fermented grape skin extract solution (KFSE) was examined for its antioxidant ability in a human embryonic kidney (293T) cell oxidative damage model caused by H2O2 and its inhibitory effect on human hepatoma (HepG2) cells. The results showed that KFSE reduced the degree of oxidative damage in 293T cells, increased the relevant expression levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and GSH-peroxidase (GSH-Px), and total antioxidant capacity (T-AOC), and decreased the expression levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), and nitric oxide (NO). The expression of genes and proteins of SOD, CAT, GSH, and GSH-Px was up-regulated. In addition, KFSE-induced growth inhibition appeared to be through induction of cell-cycle arrest. This induction was accompanied by a reduction in the expression of cell-cycle genes, such as cyclin-D1 and CDK4. In addition, KFSE induced gene expression of p21, the apoptosis gene wild-type p53 and the caspase family. At the protein expression level, Bax and Caspase-8 were up-regulated, and the inflammatory marker Nuclear Factor Kappa-B (NF-κB) was down-regulated. The fermentation solution polyphenols were separated and identified as epicatechin gallate, coumarin, new chlorogenic acid, rutin, resveratrol, chlorogenic acid, rosmarinic acid, etc. by HPLC. Overall, these results demonstrate that KFSE significantly attenuated oxidative damage in 293T cells and inhibited tumor growth in HepG2 cancer cells, induces cell-cycle arrest and affects proteins involved in cell-cycle regulation and proliferation. This suggests that KFSE may also be explored as a neo-adjuvant to expansion of hepatoma.