We are introduced to the Fantastic Four in 1968, narrated by the Watcher.  They are already a premier super team and celebrities. That year they are confronted by the coming of Galactus in the classic comic fashion.  Just like in the comic, Johnny finds the Ultimate Nullifier with the help of the Watcher.  The plan to scare Galactus away with the Nullifier seems to work as first, but Galactus is not swayed.  In a fit of rash anger, Johnny uses the Nullifier, but in the cinematic universe, the effects not only nullifies the wielder and those around him, it erases their entire timeline.

We are reintroduced to a new version of the Fantastic Four in modern times as Reed, Johnny, Ben, and Sue make their historic flight to study odd cosmic energy fluctuations, fearing another Chitauri invasion. As in the comics, their shielding fails and they become the Fantastic Four. Even as they come to terms with what happened to them, SHIELD tries to recruit them as replacements for the Avengers who are currently off fighting Thanos. Unfortunately, the Silver Surfer once again heralds the coming of Galactus who feels inexplicably draw to Earth to feed. As it was in the classic encounter, the Surfer turns on his master, the Watcher helps Johnny find the Nullifier, but this time Reed has time to analyze the device on the spot, modify it and then threaten Galactus with it.  Reed was able to alter the effects of the Nullifier to only effect the target. This meant Reed could erase Galactus from the timeline ending his threat to the universe.  Galactus was so startled by the sheer mental prowess of Reed Richards and by extent, the human race, that he leaves the planet, but not before trapping the Surfer on Earth and vowing to go back and consume Zenn-La, the Surfers home world.

When the Avengers return, they are greeted by a new (old) team based in New York, the Fantastic Four.