The methanol and dichloromethane extracts of Inula cappa (Ham. ex D. Don) DC. were evaluated for inhibition of herpes simplex virus infection. Higher anti- herpes simplex virus (HSV) activity of I. cappa methanol extract was observed comparing with I. cappa dichloromethane extract since more than 50% of the virus was inhibited by I. cappa methanol extract and 50% effective doses of I. cappa methanol extract on HSV-1and HSV-2 were 720.1±32.7 and 529.2±5.2 μg/ml respectively. However, when the virus particles were treated with I. cappa dichloromethane and I. cappa methanol extracts, both HSV-1 and HSV-2 particles were directly inactivated to negligible amount within 1- 2 h. More than 50% interference on blocking of HSV attachment and penetration was observed after treatment the virus with I. cappa methanol extract. Moreover, within 30 h, the effective inhibitory activity of I. cappa methanol extract on HSV replication was higher than that of the I. cappa dichloromethane extract. Both extracts had potent activities in reducing viral deoxyribonucleic acid (DNA) synthesis since HSV DNA after treatment with the extracts were 1.3-2 fold less than HSV DNA control after determination by real time polymerase chain reaction and approximately 45 kilodalton viral proteins were clearly diminished after treatment with I. cappa methanol extract. Therefore, methanol extract of I. cappa is a potent inhibitor of herpes simplex virus infection in vitro. © 2011 Academic Journals.