Pettis becomes the first fighter since 2007 to miss weight for a championship bout. Nearly a decade ago, Travis Lutter failed to make weight for his middleweight title shot against Anderson Silva. On that night, Silva defeated Lutter by second round submission in a non-title fight.
Pettis will also be fined 20-percent of his purse for not making weight for the championship bout.
"I'm not happy, but listen, it happens," UFC president Dana White said on TSN SportsCentre.
"Believe me when I tell you, Anthony Pettis wanted to make weight. He's been working for months for this day. He came in, when he landed here in Toronto, he was 10 pounds (over), so he should've made the weight. What that tells you is he's too old and he's too big to make that weight, is my opinion. So we'll see where we go from here."
White indicated Pettis may not get a shot at full FW champion Jose Aldo should he win and may be done in the division, having already dropped from lightweight.
"If Pettis wins, I've got to decide if I want him to fight for the 145-pound (title)," White said. "I don't know if he can make the weight."
Pettis told MMA Fighting that he had abandoned his weight cut.
"It was a team call," Pettis said. "My body just wouldn't let go of that extra weight. It's just one those things. We did everything right beforehand, everything was on point. My body just gave out. I had nothing left to give.
"In the end, we decided that my career and health are more important than those two extra pounds.
"I'm not here for the interim belt," he said. "Originally, this fight wasn't for the belt. The plan has always been to just beat Max Holloway.
"And he's not beating me tomorrow night."
The fight had already been mired in controversy, after Conor McGregor was hastily stripped of his FW belt to enable the interim title (then held by Aldo) to be contested.
Recent FW convert Pettis was also a contentious choice to face No.2 Holloway, ranked No.5 and perhaps benefitting from a higher profile than No.3 Ricardo Lamas and No.4 Cub Swanson. Ex-lightweight champ Frankie Edgar, who lost an interim FW title fight to Aldo at UFC 200, remains the No.1-ranked contender.
Holloway vs Pettis became the UFC 206 main event after Daniel Cormier withdrew injured from his light-heavyweight title defence vs Anthony Johnson.
Pettis wasn't alone missing weight on Friday as two more competitors also failed to hit the mark when stepping on the scale, although the stakes for those fights were certainly much different than the championship main event.
Valerie Letourneau, who has suffered through some brutal weight cuts to get down to 115 pounds, came in at 117.5 for her bout against newcomer Viviane Perreira. Letourneau has struggled to get down to the strawweight limit before and this latest incident saw her missed the required weight by one and a half pounds.
Rustam Khabilov also came in over weight at 158.5 pounds - two and a half pounds over the limit for his bout taking place in the lightweight division.
Both fighters were fined 20-percent of their respective purses, which goes to the opponent on Saturday night.
Here are the full weigh-in results for UFC 206 on Saturday night in Toronto:
UFC 206: Holloway vs. Pettis Main Card
MAIN EVENT: Max Holloway (145) vs. Anthony Pettis (148)*
Matt Brown (171) vs. Donald Cerrone (170.5)
Dooho Choi (145.5) vs. Cub Swanson (146)
Kelvin Gastelum (185) vs. Tim Kennedy (186)
Emil Meek (170.5) vs. Jordan Mein (170)
UFC 206 Prelims
Misha Cirkunov (205) vs. Nikita Krylov (206)
Olivier Aubin-Mercier (156) vs. Drew Dober (156)
Valerie Letourneau (117.5)** vs. Viviane Pereira (114)
Mitch Gagnon (135.5) vs. Matthew Lopez (136)
UFC 206 Early Prelims
John Makdessi (155) vs. Lando Vannata (156)
Rustam Khabilov (158.5)** vs. Jason Saggo (155)
Zach Makovsky (125) vs. Dustin Ortiz (125)
* Pettis misses weight, no longer competing for interim featherweight title. Fined 20-percent of his purse.
** Fined 20-percent of the purse, which goes to their opponents.
