Nunes (16-4) hurt Pennington with leg kicks and busted her nose with a knee, en route to a TKO finish. Referee Marc Goddard stopped the 135-pound title fight at the 2:36 mark of the final round at Jeunesse Arena.
Pennington (9-6) was so demoralized in the bout that she actually told her corner she was finished before the start of the fifth round. Her corner talked her into going back out, but it was all for naught. Nunes took her down and landed hammerfists until the bout was stopped.
The coach who encouraged Pennington to continue was identified by multiple media outlets as Jason Kutz.
"It's sad because you could avoid something," Nunes said about Pennington's corner. "She went to the hospital. It might be a bad injury. ... It's sad. If she didn't have the right conditioning to fight, the coach should have thrown in the towel for sure. I think my coach wouldn't have let me go through that.
"It's sad. ... I think she really needs to surround herself with people that want the best for her so she can evolve in her next fight. Unfortunately, tonight he failed."
Immediately after the fight, an emotional Nunes said it was the most difficult fight of her career. It was the first time in UFC history that two openly gay fighters competed for a championship. Pennington is engaged to UFC strawweight Tecia Torres, who used to train with Nunes in South Florida.
"I've never fought nobody as a friend. This is the first time," Nunes said. "I like and respect these girls so much, especially Tecia. She used to train with us. This was very hard for me. It was the most hard in my career.
"To defend this belt is something I dream, and I have to do it. But we are going to leave this cage and have a beer and celebrate our friendship. Tonight was about my belt, but I respect the friendship we have."
According to Fightmetric, Nunes outlanded Pennington in total strikes 152-79. She swept Pennington off her feet with the very first leg kick she threw and had success keeping the challenger's back to the fence all night.
Pennington's corner implored her to move forward on the champion, something she did well in the second round. She started to land her jab and follow-up right hand, but she was always forced to move forward as she threw, which seemed to have a negative effect on the power of the shots.
A Colorado native, Pennington tried to get Nunes to the floor throughout the bout but managed to convert only one takedown. She paid for the failed takedown attempts, too, as Nunes made a habit of digging knees into the body and head after Pennington bailed on single leg shots.
Nunes has now won seven in a row and has recorded 11 career knockout victories. Her UFC title run includes victories over high-profile fighters such as Miesha Tate, Ronda Rousey and Valentina Shevchenko. The UFC has expressed interest in a potential super fight between Nunes and 145-pound champion Cris "Cyborg" Justino later this year.