Lupus played Willy Armitage in the original Mission: Impossible television series in the 1960s. Armitage was the Impossible Missions Force's muscle man, and featured in nearly all episodes of the series. The character of Willy Armitage was the strong, silent type, usually with very little dialogue. Late in the show's run during season five, the producers decided his character was superfluous and he was dropped to recurring status, appearing in a little over half of that season's episodes. Fan outcry and the lack of success in finding a replacement for his character resulted in his return to regular status the following season and getting a greater role in the stories, often assuming roles as a convict or thug. Only Lupus and Greg Morris sustained a regular role through the show's entire run, although Morris appeared in more episodes.

During the early 1970s, Lupus promoted European Health Spa, traveling the country to make appearances and sign autographs at several of the gyms' grand openings.

Lupus was one of the first well-known male actors to pose with full frontal nudity for Playgirl magazine, in April 1974. Photographs of Lupus would appear in a number of issues. Before this, he was hired by the United States Air Force to appear in a series of commercials playing the role of Superman (with the permission of what is now DC Comics). He appeared for many months until the Playgirl pictorial was published.

On July 19, 2007, at age 75, Lupus set a world weightlifting endurance record by lifting 77,560 pounds over the course of 24 minutes, 50 seconds at the Spectrum Club in El Segundo, California. This topped the record Lupus set five years earlier in celebration of his 70th birthday of 76,280 pounds in 27 minutes.