Tom Holland as Spider-Man*
Let's start by addressing the elephant in the room and clarifying that Tom Holland hasn't been officially confirmed to return in Avengers: Doomsday yet. The Hollywood Reporter stated that he will likely be back in Earth's Mightiest Heroes' next movie, but that means his appearance isn't 100% secured yet. That being said, it would be absolutely shocking if Spider-Man didn't swing by to save the day in an apocalyptic-level event.
Now that the MCU has lost some of its heavy hitters like Iron Man and Captain America, many fans see the wall-crawler as the next in line for the role of most important hero. Besides, he also played a huge part in breaking the multiverse during the events of Spider-Man: No Way Home. And we all just know that Marvel is planning a scene where Peter discovers that the biggest threat in the multiverse shares the same face as his former mentor. So we should definitely count Spidey in for Avengers: Doomsday. In the worst case, he has a relatively small role akin to a cameo. But chances are that he'll be one of the main faces of the movie.
Anthony Mackie as Captain America
We need to acknowledge yet another Marvel star who revealed he'll be coming back in Avengers: Doomsday during an interview. Anthony Mackie, better known for portraying Captain America on the MCU, told Empire he's "really looking forward" to working with the Russo brothers once again (you know, the directors of Avengers: Doomsday). Of course, Earth's Mightiest Heroes need a mighty leader, so who better than Sam Wilson to fill that place?
During the events of The Falcon and the Winter Soldier, we see Sam reluctantly grow into Steve Roger's former shield and make it his own. So it will be interesting to see if he instinctively leads other characters such as Doctor Strange and Spider-Man on the big crossover events, or if he'll need some time to get used to that as well. At the time of writing this, we're just a few weeks from the premiere of Captain America: Brave New World, so at least we won't have to wait long to see how Sam has been doing as one of the leading faces of the MCU and get a better idea of how good he'll do in a fight against Doctor Doom.