Increasing evidences suggest that mesenchymal stem cells (MSCs) could migrate to the tumor site and play a vital role in tumorigenesis and progression. However, it is still a lively debate whether MSCs exert a pro- or anticancer action. Cancer development and progression is a multistep process. Therefore, we investigated the effect of MSCs on hepatocarcinoma and whether the role of MSCs depends on the stage of cancer development. In our study, chronically exposing rats to N-diethylnitrosamine (DEN) was employed as hepatocarcinoma model. And to evaluate the effect of MSCs on hepatocarcinoma, the animals were divided into three groups: rats were injected with MSCs in the initial (DEN + MSC (Is) group) or progressive stage (DEN + MSC (Ps) group) of hepatocarcinoma, respectively. Rats injected with PBS were used as control (DEN group). Interestingly, we found that MSCs had a tumor-suppressive effect in the Is of hepatocarcinoma, yet a tumor-promotive effect in the Ps. In the Is, MSCs showed a protective role against drug damage, possibly through reducing DNA damage and ROS accumulation. Meanwhile, MSCs in the Is also exhibited anti-inflammatory and anti-liver fibrosis effect. Further, in the Ps, MSCs facilitated tumor formation not only by enhancing cancer cell proliferation but also through promoting stem cell-like properties and epithelial-mesenchymal transition of liver cancer cells. Taken together, MSCs have a paradoxical role in the different stages of hepatocarcinogenesis, which sheds new light on the role of MSCs in hepatocarcinoma and cautions the therapeutic application of MSCs for liver cancer.