[7][8] Colicos' skill in acting resulted in his being chosen to play the title role in a memorable and first-ever production of King Lear (1964) at the Stratford Festival.

He also gave memorable performances in 1966 on the CBS soap opera The Secret Storm; as the unscrupulous Thomas Cromwell in the 1969 movie version of Anne of the Thousand Days; and as the governor of Umakran in the episode "The Goddess Calabra" from the 1973 TV show The Starlost.

On American television, he established himself as a science-fiction villain icon, portraying the first Klingon ever seen in the Star Trek franchise, Commander Kor in the Original Series episode "Errand of Mercy" (1967).

Budget constraints prevented the extensive makeup the Klingons were supposed to have so Colicos suggested they have a leathery Genghis Khan look, dark skin and hair.

In August and September 1981, he portrayed Mikkos Cassadine, a demented, power-mad businessman bent on freezing the world, on the ABC soap opera General Hospital.

Colicos' final acting appearance was his reprise of Count Baltar in the concept demonstration trailer Battlestar Galactica: The Second Coming, exhibited at many science fiction conventions in 1999.