The news comes one day after UFC president Dana White shot down the potential of a future fight between Justino and UFC bantamweight champion Ronda Rousey.
At a media luncheon Thursday in Las Vegas, White expressed doubt that Justino, who tested positive for an anabolic steroid in 2011, is a clean fighter. He also ripped Ortiz's abilities as a manager.
In a statement released to "Inside MMA," Ortiz, who battled with White during his fighting career in the UFC, issued his response in the form of a resignation.
"I can live with Dana not liking me but what I can't live with is Dana using me to hurt someone else," Ortiz said.
"I've taken abuse and maybe I deserved some of it, but Cris is a beautiful person and great athlete and she doesn't deserve to be insulted like this.
"I won't stand in the way from the fans getting a fight they want and I won't hold Cris back. So, I'm stepping down as Cris' manager."
Even with Ortiz out, a fight between Rousey and Justino is far from a reality.
Justino (12-1) has said she has one fight remaining on her current deal with Invicta FC. The problem, however, is the same one that existed when the UFC attempted to sign her to a contract in 2013 -- the weight at which she fights.
During a news conference in February 2013, Justino and Ortiz made it clear it is unsafe for her to cut to 135 pounds due to health reasons. The UFC does not currently promote a 145-pound female weight class.
Nevertheless, the UFC offered Justino a deal that would have kept her under contract while allowing her to compete in outside organizations. Justino declined, signed with Invicta FC and won the promotion's featherweight title in July.
"They come out with this press conference where he says she will die if she goes to 135," White said. "So, I'm going to go before an athletic commission and say I want to make a fight between Ronda Rousey and Cyborg at 135 pounds? She's on record saying she'll die."
In 2012, Rousey (8-0) became the first female to sign a UFC contract. A former U.S. Olympian in judo, she defended her title twice in 2013 and is scheduled to do it again next weekend against Sara McMann at UFC 170 in Las Vegas.
According to White, Rousey's star power has been so strong in the UFC that it's possible she will crack the company's 10 highest-earning fighters of all time by the end of her third fight.
"She's a world champion and she's got to answer questions about Cyborg, who will die if she goes to 135 pounds?" White said. "It makes no sense.
"Ronda doesn't need Cyborg. Most people don't know who the f--- Cyborg is. It's funny how you guys talk about everything being fair and drug use, but you want to see Cyborg fight Ronda."
In regards to White's comments questioning whether Justino is a clean fighter, Ortiz, in his last move as her manager, challenged the UFC head to pay for a test.
"I challenge you to put up or shut up," Ortiz said. "Test her or stop lying about her."