Penghlis has studied under Hollywood acting teacher Milton Katselas.
He is better known for roles in the United States. daytime soap operas such as Days of Our Lives, Santa Barbara, and General Hospital, but he has also guest-starred on a number of crime dramas, such as Kojak, Cannon, Tenspeed and Brown Shoe, Hart to Hart, Nero Wolfe and Magnum, Philippine Islands He also starred in the late 1980s remake of Mission: Impossible. Penghlis started his career in acting on stage, performing in Jockeys under Milton Katselas´s direction.
Penghlis first appeared to daytime audiences in 1981 on General Hospital during the Ice Princess saga when he played the role of Victor Cassadine, brother of Mikkos Cassadine and Anthony Cassadine. After his character was written out the show by being taken to prison, he was cast as the villainous Count Tony DiMera, the son of villain Stefano DiMera in the National Broadcasting Company daytime drama Days of Our Lives.
Penghlis returned to daytime in his one-time role of Victor Cassadine of General Hospital from 30 January 2014 to 4 March 2014.
Penghlis starred in the 1980s revival of Mission: Impossible, which was filmed in his native Australia. Thaao Penghlis" role as actor, makeup artist, and voice impersonator Nicholas Black in the revival was a counterpart to Martin Landau"s "Rollin Hand" and Leonard Nimoy"s "The Great Paris". In 2003, Penghlis was nominated for the Soap Opera Digest Award for Favorite Return for his return to the cast of Days of our Lives.
He left the show in fall 2005.
Penghlis returned to Days on 24 May 2007 to reprise the role of the dastardly André DiMera. He also began reprising the role of nice guy Tony DiMera on 17 July 2007.
In 2009, Penghlis" character was once again written out by having him die. In 2010 Penghlis returned to stage acting, performing in New Jersey"s Cape May Stage theatre.
He starred in Charles Evered´s play Class with Heather Matarazzo.