Shadowverse: Nexus, the opponent in Chapter 8 of the Forestcraft Story path, uses an illegal deck that has cards from all classes, resulting in otherwise impossible combos that can easily overwhelm the player, especially if they have been going through Story Mode with little modifications from the default deck. And it's just the first of many bosses to use such a deck.
Tyrant has the Epic Siege on Kor raid. The commander summons a Rat Catcher every turn, which can immobilize you and Phase you as well, blocking that unit from being affected by your own friendly activation skills. The core structure cards are some of the deadliest in the entire game, including the Cannon Wall, which has 15 health, and in 3 turns it Enfeebles all of your units, making them take 2 additional damage from all attacks and then proceeds to Strike all of them for 3 damage (after the effects of Enfeeble). There's also the Cluster Mine, which has Counter 10, which will pretty much kill any of your units that hit it. You think you can just Siege away those structures? Well, it also has two of its own version of the Gatling Tower, which will Strike one of your own units for 4 damage, inflict Chaos on all of your units, turning all of your own attack skills against yourself and thus blocking any Siege strategy you might employ, and Sieging all of your structures for 2 points of damage, all after only 2 turns. If that's not enough, the randomly generated player-available cards can make it even worse, including the Metalworks, the Usial, and Orwold's Reckoning, all of which can summon even more enemy units in addition to the commander's Rat Catchers. The best possible deck for this raid has only a 77% win rate, while all other raids have at least one deck with a 95%+ win rate, and it has 1.2 million health which requires great contribution from all 40 possible people to take it down within the 3-day time limit.
The beta versions of Plants vs. Zombies: Heroes has the infamous mission 20 Green Shadow boss. First of all, there is a rule called Power to the Plants! note Which gave all plants +1/+1 for the rest of the game. This rule alone makes every single plant a threat, no matter how weak or strong. Alongside, she starts with 3 Torchwoods and +15 health, so she starts with 35 health. On the other hand, you get no boost or advantage. Lastly, all lanes are heights so your amphibious zombies are more prone and ground lane tricks are useless. In the public release, the mission got nerfed to only have Green Shadow start with only +2 cards and no additional plants or health boost.
Slay the Spire: While all the tier three bosses are hard, the Time Eater is like pulling teeth. It has a counter that ticks up every time you play a card, and when it hits 12, your current turn immediately ends and it gets a strength boost, which will increase each iteration of damage it deals by 2 - and its attacks are already pretty hefty and, devastatingly, deal damage multiple times. This counter does not reduce naturally; all you can do to get rid of it is trigger it. That would, in and of itself, let the Time Master hard-counter Spam Attack decks like some Silent and Defect builds, but to make matters worse, it also has an effect at below half health where it heals back up to half and shakes off all negative status effects, making an already tough fight that much harder. And God forbid you misplay and accidentally trigger its turn. If it kills you right after, you won't be able to reload the fight.