Lipid reprogramming has been considered as a crucial characteristic in hepatocellular carcinoma (HCC) initiation and progression. However, detailed molecular mechanisms have yet to be clearly defined. Here, we examined the effects of tumor suppressor TIP30 on the regulation of HCC lipid metabolism. We found that decreased TIP30 expression leads to elevated fatty acid synthesis and enhanced levels of lipogenic enzymes SCD and FASN in HCC cells. Moreover, SREBP1 is one of the key transcription factors regulating liver lipid metabolism, and TIP30 deficiency significantly increased SREBP1 expression and nuclear accumulation. Small interfering RNAs targeting SREBP1 could reverse fatty acid synthesis induced by TIP30 deficiency. Furthermore, downregulating TIP30 activated the Akt/mTOR signaling pathway to upregulate SREBP1 expression, which promoted lipid metabolism by activating gene transcription of lipogenesis, including fasn and scd. We also showed that TIP30 deficiency-regulated lipid metabolism promoted proliferation of HCC cells. Clinically, our data revealed that TIP30 expression significantly correlated with SREBP1 in patients with HCC and that a combination of TIP30 and SREBP1 is a powerful predictor of HCC prognosis. Together, our data suggested a novel function of TIP30 in HCC progression and indicate that TIP30 regulation of SREBP1 may represent a novel target for HCC treatment.