A year after the team returned to Earth, the Fantastic Four is ordered by the military to open up a portal to the Negative Zone to build a planned super-prison. After they refused, the portal in the Baxter building is accidently opened by the Human Torch and they are transported to the Negative Zone, with Annihilus and his armies of insectoids waiting to attack.
Set in the Marvel Cinematic Universe, the movie begins with a tour group being led by a guide around the Baxter building and watching short videos detailing the origins of the Fantastic Four. One of the visitors asked the guide where the group is and the scene cuts to the Fantastic Four being held captive by Annihilus. The Fantastic Four breaks put from their chains and a brawl ensues between the Fantastic Four and Annihilus. Back in the Baxter building, the visitor unmasks himself revealing his scarred face much to the horror of the visitors. He tells the tour guide to tell Reed Richards to contact him when they arrive on Earth and gave her his number. Back in the Negative Zone, the Fantastic Four barely manages to escape and is now chased by Admiral Deko and Insectoids. The Fantastic Four managed to reach the portal in time and escapes from the Insectoids. When Reed gets the number from the guide, he immediately recognizes the number as the contact number of Victor von Doom.
Victor von Doom balks at Richards whom he blames for scarring his face. Reed denies this and offers to find a way to heal his face. Victor refuses and hangs up, promising that he will make Reed and his group suffer. Reed ponders in his lab, wondering if he, in fact, is the reason for Doom's scarred face. Sue Richards told Reed that the accident was not his fault and that Victor never liked him from the start of their college. She reminded him of the time when Victor tried to sabotage Reed's science project in high school. Meanwhile, Johnny Storm angrily complains that the news is filled with Avengers, Spider-man or reminding people of that time when this "mad titan" tries to destroy the universe with this gauntlet instead of their trip to the Negative Zone. Ben Grimms told him that their trip is mostly secret anyways. Reed and Sue discuss the possibility of having kids wheen Thaddeus Ross contacted them and reveals that the military knows their "secret" trips and wanted them to create a portal in a military base in Nevada. Reed refuses, telling them that their trip was not meant for military purposes but rather to explore new worlds and dimensions. Thaddeus Ross reveals that the building is surrounded and they have to build that portal anyways. When Reed asked why they could not have Tony Stark instead, Ross reveals that it is easier to have the Fantastic Four "missing" as it could be explained that they went to save another planet rather than capturing an Avenger. As the military broke through, Reed uses his stretchy powers to catapult Ben to the army personnel. Johnny shouts "Flame on!" as he burst into flames and Sue uses her forcefields to knock the armies down. She then turns herself invisible and opens the portal to transport them to the Negative Zone. Soon, the Fantastic Four and some military members are transported to the Negative Zone. Sue apologizes and reveals that she sometimes acts irrationally when under pressure. When Reed asks why, Sue reveals that she is in fact pregnant. Suddenly, the Thing spots something in the distance, Annihilus, Admiral Deko and thousands of Insectoids going after them. Soon, a massive battle breaks out between the Fantastic Four and some military members versus the armies of Annihilus. Reed then realizes that he can destroy the Insectoids if he can just reach the main ship. Sue uses her forcefields to transport herself, Reed, the Thing and the Human Torch onto the ship. Reed refuses to allow Sue to fight as she is pregnant. Ben shouts that "It's' clobbering time!" as he smashes and clobbers any insectoids in their way. the Human Torch lights e insectoids and Admiral Deko on fire and thus Reed reaches the control center. After Reed uses the main controls to "shut down" the insectoids, he programmed the ship to self-destruct. However, Annihilus confronts them before they can escape and easily beats the Thing, the Human Torch and Mr. Fantastic in battle. Sue then force chokes Annihilus and throws it to a sharp part of the damaged ship. A dying Annihilus manages to shoot Sue unconscious as she is transporting the group away and thus the Fantastic Four is trapped in the Negative Zone as the portal is destroyed by insectoids that manage o go through the portal to Earth. With the insectoids defeated by the Avengers and the military, Tony vows to bring them back to Earth and he will dedicate his time to rebuild the portal and rescue them from the Negative Zone. In the mid-credit scene, Victor found a mask that a group of monks gave to him during a trip to Tibet and wears it along with a green cloak, declaring himself as Doctor Doom. In the post-credit scene, Thaddeus Ross is revealed to be a Skrull.
- Adam Driver as Reed Richards / Mister Fantastic
- Amanda Seyfried as Sue Storm / Invisible Woman
- Bill Skarsgard as Johnny Storm / Human Torch
- Theo James as Ben Grimm / The Thing (CGI)
- Henry Cavill as Victor von Doom / Doctor Doom
- Emma Watson as Alicia Masters
- Daniel Craig as Silver Surfer
- Ian Mcshane as Mole Man
- Keanu Reeves as Namor McKenzie / Namor the Submariner
- Jonah Hill as H.E.R.B.I.E (voice)
- Laurence Fishburne as Galactus (voice)
- Phil LaMarr as The Watcher (voice)
- Penelope Cruz as Sharon Ventura
- Robin Atkin Downes as Annihilus (voice)
- Tim Curry as Admiral Deko (voice)
- William Hurt as Thaddeus Ross
- Robert Downey Jr as Tony Stark/Iron Man
- Tom Hanks as Phillip Masters
- Stan Lee as Watcher Informant