Thanos represented the moment that all of the Marvel Cinematic Universe was building up to for over a decade, and he was well worth the wait. The DCEU was clearly building up to a comparable endgame with Darkseid, but maybe something more original could have a bigger impact.
The impulse with superhero stories tends to lean towards bigger is better, but that only leads to meaninglessness as expansion ceases to be impressive. The DC Extended Universe has had some better luck by stripping things down and telling more personal stories, so maybe the villain to take the franchise to a more interesting place could be a human controlling the world from the shadows.
Amanda Waller was created by John Ostrander, Len Wein, and John Byrne in 1986. She is best known, in the comics, as the commander and overseer of Task Force X, AKA The Suicide Squad. She came up with the project and makes it her business to lead research into people with superhuman capabilities. She lacks any superhuman power but is ruthless, determined, and skilled enough to command people far more powerful than she is. She commands immense personal powers, she's a tremendously capable tactician, and she refuses to allow anyone to get in the way of her goals. Amanda Waller isn't a hero, but she's only occasionally a villain. Her motivations are cruel and unforgiving. She wants what's best for the United States first and for humanity second. She's popped up in a huge variety of DC on-screen adaptations but is best known for her modern portrayal in the DCEU.
DCEU fans were first introduced to Viola Davis' note-perfect performance as Waller in 2016's Suicide Squad. She's immediately powerful, threatening, intelligent, and ruthless. Now, that movie is less than well written, meaning most of her moves don't make a ton of sense, but the other characters seem to realize what she's capable of. She develops and pitches the idea of organizing a team of supervillains and murderers, then successfully guides them to victory. Waller guns down a crew of her own analysts just to keep witnesses to a minimum. She regularly orders actions that could kill off her own team. To Waller, everything is expendable, making her an unpredictable leader.
In that film's end-credits scene, Waller reaches out to Bruce Wayne. She trades her information on metahumans for legal protection from the consequences of her actions. The final moment of that scene sees Wayne encourage her to shut down Task Force X, and tacitly threaten her that the Justice League will intervene if she doesn't. This seems to plainly set up the idea of a Suicide Squad versus Justice League storyline, with Waller in the leadership position of the villainous team.
She returns in The Suicide Squad, in more or less the same role. Waller organizes a new team of villains, largely through threats, to lead a violent assault on a small island nation for morally bankrupt reasons. Waller is willing to send the first half of the team into their guaranteed slaughter for no other reason than to free up an entry for the second half. When her true intentions are revealed, it becomes clear that her goal had nothing to do with saving lives. Waller sent Task Force X to clean up Project Starfish because the US would've been implicated in its destruction. Waller will destroy whatever it takes to ensure her nation's supremacy.
Though all of her actions could easily be described as amoral, she doesn't really become the film's villain until the end. She orders the remaining members of Task Force X to allow the nation to be destroyed and threatens the team with death if they try to help. Waller is betrayed by her team, but if her subordinates had remained loyal, immense destruction would be on her hands.
Amanda Waller is a violent, domineering, manipulative supervillain, driven only by a nationalist desire for power. Her actions occasionally land on the side of good, but she's just as willing to do evil if it benefits her cause. Her motivations could easily place her in opposition to DC's stable of heroes, or indeed the fate of the rest of the world. Waller commands a tremendous amount of institutional power, and with it, could be a new kind of villain. Obviously, a normal human woman couldn't stand up to Superman or The Flash on her own, but with the information and resources she has access to, she could be a tremendous threat. Waller gave Wayne the building blocks he needed to start seeking out metahumans to form the Justice League. Between her insider information and her access to countless villains, Waller could be a massive threat to the DCEU.
There's nothing wrong with aliens, or monsters, or robots, or wizards being the big threat at the end of a superhero story, but sometimes a more human threat can raise the stakes. Amanda Waller has the power, the motivation, the perfect performance, and the narrative build-up to be the DCEU's big franchise-wide villain.