The only similarities (or just references) that the film has with the source material outside of the name.
- The first time we see Johnny Storm in the trailer, he is repairing a car. He was doing the same in the first issue in the comics.
- The white spacesuits seen in the trailer resemble the Future Foundation's uniforms.
- The black uniforms are reminiscent of the last time the Fantastic Four spent extended time in the Negative Zone.
- When a young Reed tells his class about his homemade teleporter, his teacher scoffs and asks if it's next to his flying car. Reed responds by saying that he did try to build a flying car, but stopped working on it. This is referencing the Fantasticar, the group's trademark flying vehicle from the comics and animated adaptations note .
- When expressing his disgust at how the "Quantum Gate" is going to be used for military purposes, Victor speculates that they’ll probably use the other dimension as a prison for convicted war criminals. This is essentially what Reed did with the Negative Zone in Civil War (2006).
- Victor grows jealous of Reed for his instant success in the Baxter Building's teleporter project that Victor started. In the comics, part of Victor von Doom's hatred comes from Reed interfering and messing with an inter-dimensional traveling device that Victor built in college.
- Not wanting astronauts or soldiers who have been uninvolved in the teleporter project to get all of the glory, Reed, Ben, Johnny and Victor hijack the device to be the first humans across. In the comics, the first three and Sue stole a rocket to beat the Soviets to space (it was the early '60s).
- Susan being the one to design the environmental suits for the mission could be seen as an homage to her being the one who originally made the team's classic blue and black uniforms in the comics while also updating it from the Textile Work Is Feminine trope of the time.
- Ben does work for the military during the time skip, alluding to him being an Air Force pilot and an astronaut in the mainstream continuity.
- Doom's feud with Reed comes from their college days, where Victor builds an interdimensional travel machine that Reed offers input on, with Victor getting scarred when things go wrong and blaming Reed. Here, Victor gets disfigured in an incident involving an interdimensional travel machine and Reed being unable to pull him up in time.
- Doom becomes the Big Bad of the film, and he gains his powers along with the titular group, which is what happened in the 2005 film and the Ultimate comic.
- It's varied for a time, but Doom's scarring comes from two sources: The teleporter accident that leaves a tiny, single scar on his face. He later puts on his mask for the first time before the metal's cooled, fully scarring his face. In this film, his helmet melts/fuses with him during a teleporter accident, combining the two sources.
- Sue's costume is based on the late-2000s design by Bryan Hitch.
- Ben suggests that the group call themselves "The Big Brain & His Neurons". "Big Brain" was an alias used by Reed Richards in the Marvel Comics 2 line, and before that, it was his superhero name in a What If? reality where the accident literally turned him into a giant telepathic brain.
- The lab that the team get at the end of the movie is called "Central City", which is the name of Reed's hometown and their original place of operation during their Early-Installment Weirdness.
- Doom's final form resembles a rockier version of the Silver Surfer, and deliberately so: in the original draft of the script, he was specifically sent back to Earth as a Herald of Galactus.
