The Green Goblin could be a great main villain. Imagine he somehow gets hold of time - travel technology too. He could go back in time to eliminate Spider - Man before he even becomes a hero, or change events in the past to make his own power even greater in the present.
Mysterio could be an interesting main villain. He could use time travel to create elaborate illusions across different time periods. Spider - Man would have to figure out which events are real and which are Mysterio's illusions while also trying to stop him from causing chaos throughout time.
Venom is also a strong candidate. In this fanfiction, he could be more powerful than ever. He might be infected with some sort of alien symbiote that gives him enhanced abilities. Venom could target Spider - Man because he wants to prove that he is the stronger one. And by attacking Spider - Man, he also draws the attention of the Avengers, which he sees as a challenge. He could start by attacking the city and luring Spider - Man and the Avengers into a trap.
How about a new villain created specifically for the fanfiction? A being made up of the combined negative energy from all the spider - verses. This entity could be called the 'Void - Spider' and it feeds on the chaos and destruction that often follows Spider - Man in his battles. It would be a very powerful and unique threat that the Spider - Men from different universes would have to face together.
The Green Goblin could be a great main villain in a crossover. Imagine if he teams up with Doctor Doom from the Fantastic Four universe. Their combined evil intelligence and power would be a huge threat to Spider - Man and whoever he teams up with in the crossover.
It could be Doctor Doom. He might be seeking to take over multiple universes in a crossover. Spider Man stands in his way, and Doom, with his superior intellect and powerful magic, manages to defeat Spider Man. His death would then be a huge shock to other heroes in the crossover, like the Avengers or the Fantastic Four who then have to avenge him.
Loki could be a great main villain. He could trick Spider - Man into believing that Thor is a threat to Earth and set them against each other. Then, while they are fighting, Loki could carry out his real plan which might involve stealing a powerful artifact from both Asgard and Earth.
The Green Goblin is one of the main villains. He has his own set of powers and is always causing chaos in Spider Man's city.
The Green Goblin could be the villain. He could have developed a new type of pumpkin bomb that explodes with a force that seriously injures Spider Man. This would be in line with their long - standing rivalry in the Spider - Man universe.
Darkseid could be the main villain. Imagine Darkseid learning of Superman's ability to time - travel and using it to his advantage. He could try to invade different time periods to gain more power and resources. Superman would have to fight him across time and space to protect all of existence.
The Emperor could still be a main villain even in a Padme time travel fanfiction. If Padme travels to a time when the Emperor is already in power, he would surely oppose her as she represents a threat to his rule. He might try to manipulate events to keep her from changing the future or past, depending on where she travels to.