An ex-military man called Royce awakens to find himself free falling into an unfamiliar jungle and meets several others who arrive in the same manner: Los Zetas cartel enforcer Cuchillo, Spetsnaz Alpha Group soldier Nikolai, IDF sniper Isabelle, RUF officer Mombasa, San Quentin death row inmate Stans, Yakuza member Hanzo, and physician Edwin. The group follows Royce, who Isabelle suspects is a former black operations soldier turned mercenary. In the jungle, they find a strange monument, empty cages, and deadfall traps set by a deceased Special Forces soldier. Reaching high ground, they find themselves looking at an alien sky and realize they are not on Earth.

After surviving an attack from a pack of quadrupedal alien beasts, Royce deduces they are on a moon used as a game preserve, where humans and other dangerous species are hunted. Cuchillo is killed, and his body is used to lure the survivors into a trap, which they avoid. The group follows the beasts' tracks to a camp and finds a captive Predator. Their hunters, three larger Predators known as "Tracker", "Berserker" and "Falconer", attack the group, killing Mombasa, while the others escape. Isabelle recognizes the Predator as the one matching the description of a similar creature that killed a special operations team in Guatemala in 1987, but was defeated by a single survivor.

The group encounters Ronald Noland, a solitary U.S. Air Cavalry soldier who has survived on the moon for ten seasons by hiding and scavenging from the Predators and their victims. He takes the group to his hideout and explains that the Predators hunt in threes, sharpening their skills by abducting worthy prey from other worlds, and bringing them to the planet. Noland also reveals that there is a blood feud between the Predators with a different class called the Super Predators. Royce devises a plan to free the captive Predator, hoping it will take them home.

Noland traps the others and attempts to use smoke to suffocate them, hoping to kill them for their equipment. Royce uses an explosive to attract the Predators to the hideout. Noland is killed by Tracker, who releases the group. In the ensuing chase, Nikolai sacrifices himself to kill Tracker and save Edwin. Berserker intercepts the survivors, but Stans distracts it, allowing the others to escape before he is killed. Hanzo stays behind to duel Falconer with a katana he took from Noland's stash, killing it, before dying from his wounds.

Royce, Isabelle, and Edwin continue to head for the Predators' camp, hoping to enact Royce's plan, until a trap injures Edwin. When Isabelle refuses to abandon him, Royce leaves them both behind. They are caught by Berserker, who traps them in a pit and continues to the camp. Royce saves the captive Predator in exchange for transport to Earth. The Predator dons its armor and activates the ship with its wrist computer, setting a course for Earth. Royce runs to the ship but Berserker arrives, eventually overpowering and decapitating the other Predator before using its wrist computer to destroy the ship, seemingly killing Royce. Edwin paralyzes Isabelle using neurotoxic poison from a plant he found earlier and reveals he is also a serial killer and he intends to stay on the planet. Royce appears and uses the poison on Edwin before booby-trapping him with grenades to use him as bait to injure Berserker. With Isabelle's help, Royce defeats and decapitates Berserker.

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The film was produced by Robert Rodriguez and written by Alex Litvak and Michael Finch. In 1994, Rodriguez wrote an early script for a third Predator film for 20th Century Fox while he was working on Desperado at the time. Rodriguez presented the script to the studio, but was denied when they realized that the budget would be too large. Fifteen years later, the studio decided to go with his script. Rodriguez stated:

It's the story from that script I had written way back then. They had hired me to write a Predator story while I was waiting to do Desperado back in 1995. It was crazy, this thing I came up with. So then fast-forward to now and, like, six months ago, they found the script and called me up. 'Hey, we want to redo this franchise and we found your old script. This is where we should have gone with the series! We want to move forward.' And that's what we're doing.

In 2009, 20th Century Fox studio executive, Alex Young, called Rodriguez to consider using his treatment to revive the individual Predator franchise. The film was produced at Rodriguez's Troublemaker Studios as opposed to 20th Century Fox so that Rodriguez had more creative control over the film. It was originally thought that Rodriguez would direct, but on July 1, 2009, Nimród Antal was officially signed on to direct.

Rodriguez and Antal originally said they wanted the film to be a sequel only to the original Predator as the film is trying to distance itself from Predator 2 and the first two Alien vs. Predator films.
At the 2009 San Diego Comic-Con Rodriguez stated that Predators would feature an ensemble cast, and that the most important element of the film would be "great characters so that the audience feels they're going on this journey with them". He also noted that the title had a double meaning, referring not only to the extraterrestrial hunters but also to the human characters, all of whom are dangerous killers. He and Antal wanted each of the characters to be well-developed enough to be able to stand alone. Rodriguez hoped to have Arnold Schwarzenegger play a cameo role as Dutch, his character from the original Predator film, but this ultimately did not happen.
The film was shot on a 53-day schedule. Exterior filming location was mostly set in Kolekole, Hawaii. Filming started on September 28, 2009. The film wrapped up its 22-day shoot on the Hawaii location on November 1, 2009. The film shot its interior set scenes at Robert Rodriguez's studio in Austin, Texas. Sixty percent of the film was shot in Texas in order to be eligible for a tax benefit. The film shot more exterior footage at Canyon Lake Gorge in Comal County and Hamilton Pool Preserve.

It was a blast. It was an amazing experience. We were in the tropical rainforests of Hawaii stomping through the mud and getting rained on all day and then we ended up finishing in Austin, Texas. I really think this movie is going to be good. They had cut together a trailer while we were still working and it looked amazing. It's a great cast and along with the action elements and the sci-fi elements, and with Robert Rodriguez being involved, I think it's going to push it to another level— Actor Mahershala Ali, 411mania interview
Tom Woodruff Jr. and Alec Gillis, head of visual effects studio Amalgamated Dynamics (ADI), who also previously worked on 2004's Alien vs. Predator and …

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There had been speculation that original Predator composer and conductor Alan Silvestri would return to do the score, but on February 26, 2010, it was announced that John Debney, who worked with Rodriguez on such films as Spy Kids and Sin City, would compose the original score for the film.

Rodriguez shared his thoughts on how the score should play out, saying:

I think we're going to go for something that fits the tone of the movie really well. That original score went great with the movie, but the notes and the music do really evoke a quality—you know, when he (Debney) showed me his rough cut, or some scenes, every once in a while at the right moment I started hearing strings from the score—because we had a temp score, and it really works… So we'll probably incorporate some of that. At the right time, because you don't want to overuse it. But it's like the James Bond theme—you can't use it all of the time, but when you do, you can get the audience really, really pumped.

Debney recorded many custom sounds and instruments, including Tibetan long horns to create squeals and screams. He also manipulated metal scrapes and ethnic percussion to further highlight the advanced yet brutal and primitive quality of the Predators and their world. Debney also put up a sneak-peek of one of the Predators scoring sessions. La-La Land Records released the original score for the film on July 5, 2010. The song "Long Tall Sally" by Little Richard plays during the credits; it was also used in the original Predator film.