The actor appeared in the first live-action Spider-Man as school bully Flash Thompson, while Tobey Maguire was cast in the title role.
Manganiello told host Seth Meyers on Tuesday that all the young men who appear in the film including James Franco, originally auditioned to play Spider-Man.
"I knew that you know, no matter how much of a nerd I am on the inside, I'm never going to get cast as Peter Parker because you know, I'm six-five, 200 whatever. So finding the bullies for me would be really odd," Manganiello said.
"I just didn't fit that role. I knew that I'd fit the part of Flash, or the bully better and I actually came prepared. I learned those scenes and was off-book on them when I got there," he continued about how he still came prepared to audition for Flash Thompson after reading lines as Peter Parker.
Manganiello is currently bald for a film and was previously donning a mohawk for another role. Meyers asked the Hollywood star if his wife Sofia Vergara is happy with his different hairstyles.
"I think she's happiest with jobs in which I look like I looked when we first met," Manganiello said.
"Like whenever you meet, that's the way she wants me to stay. But you know, she knew she was marrying an actor and she knew it was going to get weird at some point," he continued.
Manganiello next stars in film Archenemy, which comes to select theaters, on demand and digital on Friday.