Solanum nigrum L. (SN) has exhibited multiple biological effects such as anti-inflammation and antiproliferation. Protein kinase C (PKC) regulates cellular functions including proliferation, migration, and invasion. In the present investigation, we demonstrated that 12-o-tetradecanoylphobor-13-acetate (TPA) and constitutively activated PKC alpha significantly increased migration and invasion of HepG2 cells, while treatment with water or polyphenol extracts of SN (SNWE or SNPE) attenuated TPA-induced migration and invasion. SNWE and SNPE reduced TPA-elicited PKC alpha expression in a dose-dependent manner and obviously inhibited TPA-induced phosphorylation of p38 and ERK, respectively. Constitutively activated PKC alpha (caPKC alpha) significantly reversed the inhibitory effects of SNWE and SNPE on ERK and p38 activation. However, the antimigration effect of SNWE and SNPE could not be abrogated by caPKC alpha. Our results revealed the antimigration and anti-invasion effects of both extracts derived from SN, which may act as a promising therapeutic agent for the treatment of hepatocellular carcinoma.