The landscape of the Marvel Cinematic Universe shifted drastically with the conclusion of Avengers: Endgame. Since 2012's The Avengers, Marvel Studios had been building towards a final showdown with Thanos, which ultimately cost the Mad Titan , Black Widow and Iron Man their lives.
As the overarching villain behind the entire MCU during that period, everything revolved around Thanos, from the pursuit of the Infinity Stones to his generals like Ronan and Loki. However, the next era of the MCU will require a new generation of enemies who are threatening enough to bring all of Marvel's heroes together. While the impending arrival of the Fantastic Four in the MCU has been largely discussed, that team could also bring several u niverse-threatening villains to the MCU.
Marvel fans have wanted to see a comics-accurate Doctor Doom on screen for a long time. When Endgame's final audio byte paid tribute to Tony Stark forging his armor, some fans even thought that the clanging might have been Doom making his mask. Even if that wasn't the case, he's an ideal fit to be the MCU's next major villain, since he's well versed in science and magic and even took on Tony Stark's mantle as the Infamous Iron Man in comics.
Like a dark version of Tony Stark, Doom could literally slot in as an arrogant visionary who wants to protect his corner of the world at all costs and is less likely to abide by the Avengers or World Security Council. With Latveria as his base, Doom can even be shaped as a regent and anti-hero, gunning for Vibranium and Black Panther like he did in Doomwar. Doom's mastery of sorcery would make him an ideal adversary for Doctor Strange as well. With such a multi-dimensional villain -- someone who's even tried collecting Infinity Stones and remaking the universe on his own -- Doom offers infinite possibilities and could be used in several different franchises.
With Thanos' exit, there is a huge gap to fill in the MCU's cosmic realm. This vacuum could be filled by Galactus, who because of his insatiable desire to feed off the galaxy's energy, could be drawn to Earth, the planet where two universe-resaping snaps occurred.
The coming of Galactus can easily inspire Captain Marvel, the introduction of the Fantastic Four, the Guardians of the Galaxy and maybe even S.H.I.E.L.D.'s cosmic counterpart S.W.O.R.D. to jump into action and take a proactive stance. Thanos simply enslaved planets but the threat of Galactus out there could result in an Avengers alliance actually going on the offensive, much like Carol Danvers and her squad in The Ultimates. Since his Heralds like the Silver Surfer always proceed him, there's a natural arc for a multi-film story to follow too.
Annihilus, the alien overlord with a dark army of insectoid-like creatures, casts an imposing shadow across the cosmos that can only be compared to Galactus. Known for his destructive Annihilation Wave, Annihilus could conquer the scraps of what Thanos left behind. This villain would also offer an ideal way to introduce Reed Richards and the rest of the Fantastic Four, since they've always fought each other in the Negative Zone, which may have inspired the MCU's Quantum Realm.
Annihilus has also tangled with the Guardians and has even become an enemy of the Nova Corps, along with his nefarious allies like Blastaar alongside him. Whenever the Nova Corps flies again, they'll need proper villains to deal with after Thanos swept them aside with ease. While this alien king and his legion may not be as strong as Galactus, they can bring in other cosmic entities such as Adam Warlock, Quasar and Marvel's other intergalactic heroes as they did in the Annihilation crossover.
The Super-Skrull has been a major foe for the Avengers and the Fantastic Four in the comics for years. With his body augmented and boasting the composite powers of all four heroes, he offers the opportunity for the evil shapeshifter we didn't see in Captain Marvel. Even though the Skrulls were refugees looking for a new home after the Kree destroyed it there, it's not tough to imagine another less friendly kind of Skrull emerging with Kl'rt.
Unlike his brethren, he may not see Earth as friends, but as a kingdom to manipulate. This could make a way for the MCU's version of the Secret Invasion crossover, which saw Skrull agents infiltrating Earth and its heroic teams. The Super-Skrull as the head of this invasion could truly be a menacing sight. With Captain Marvel's Talos, the MCU's heroes didn't have a warrior leader looking to use Earth for his own ends, so the Super-Skrull could present the next batch of MCU heroes with a serious challenge.