The protective efficacy of litchi (Litchi chinensis Sonn.) flower proanthocyanidin fraction (LFPF) composed of (‐)‐epicatechin and proanthocyanidin A2 against vascular endothelial growth factor (VEGF) generation induced by nickel (Ni) in hepatocellular carcinoma (Hep G2) cells was studied. VEGF is an angiogenic inducer, which promotes tumor angiogenesis, leading to rapid tumor growth and metastasis. VEGF could be substantially induced in the Ni‐mediated Hep G2 cells. Through LFPF treatment, the Ni‐induced VEGF generation could be suppressed significantly. The inhibition of HIF‐1α expression by blocking phosphatidylinositol‐3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways, and the suppression of Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT 3), and Raf‐1 proto‐oncogene, serine/threonine kinase (RAF1)/mitogen‐activated protein kinase (MEK1/2)/extracellular‐signal‐regulated kinase (ERK1/2) pathways are important molecular mechanisms for the LFPF action. LFPF should probably reduce the risk of liver cancer in Ni‐contaminated environments by inhibiting VEGF expression.