This study is the first to investigate the antimetastatic effect of fisetin in human lung adenocarcinoma A549 cells. Fisetin exhibited an inhibitory effect on the abilities of adhesion, migration, and invasion via inhibiting the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and downregulating the expressions of matrix metalloproteinase-2 (MMP-2) and urokinase-type plasminogen activator (u-PA) at both the protein and mRNA levels in A549 cells. Next, fisetin significantly decreased the nuclear levels of nuclear factor kappa B (NF-κB), c-Fos, and c-Jun. Also, treating A549 cells with fisetin also leads to a concentration-dependent inhibition on the binding abilities of NF-κB and activator protein-1 (AP-1). Furthermore, reduction of ERK1/2 phosphorylation by ERK small interfering RNA (ERK siRNA) potentiated the effect of fisetin, supporting the inhibition of ERK1/2 being beneficial to antimetastasis. Finally, the transient transfection of ERK siRNA significantly downregulated the expressions of MMP-2 and u-PA concomitantly with a marked inhibition of cell invasion and migration. Taken together, these results implied a critical role for ERK1/2 inhibition in fisetin-reduced invasion and migration of A549 cells.