Andrographolide (1), an active constituent of Andrographis paniculata, decreased tumor necrosis factor-α (TNF-α)-induced intercellular adhesion molecule-1 (ICAM-1) expression and adhesion of HL-60 cells onto human umbilical vein endothelial cells (HUVEC), which are associated with inflammatory diseases. Moreover, 1 abolished TNF-α-induced Akt phosphorylation. Transfection of an activated Akt1 cDNA vector increased Akt phosphorylation and ICAM-1 expression like TNF-α. In addition, 1 and LY294002 blocked TNF-α-induced IκB-α degradation and nuclear p65 protein accumulation, as well as the DNA-binding activity of NF-κB. Compound 1 exhibits anti-inflammatory properties through the inhibition of TNF-α-induced ICAM-1 expression. The anti-inflammatory activity of 1 may be associated with the inhibition of the PI3K/Akt pathway and downstream target NF-κB activation in HUVEC cells.