After you make it past the preliminaries in Kaiba's tournament, you'll duel Shadi, the fifth opponent overall. While the previous four opponents scaled up in difficulty, Shadi is a noticeable step down, having monsters with stats in the hundreds, and not having significant fusions nor magic/trap cards in his deck. He's pretty much the only opponent past the early game you're guaranteed to not need to grind for.
When you return to the past, the first mandatory opponent is the mage soldier, whose monsters only have stats in the mid thousands, as well as no significant fusions nor magic/trap/equip cards. He's much weaker than the past few opponents you dueled in Kaiba's tournament, as well as the opponents to come.
When you return to the past and must retrieve the Millennium Items from the high mages in the shrines, High Mage Secmeton of the sea shrine and High Mage Martis of the desert shrine will come off as this, especially if you dueled the other, more difficult high mages before them. Secmeton uses a whole deck of water monsters, the strongest of which, Crab Turtle and Suijin, only have 2500 attack each, alongside the Twin-Headed Thunder Dragon, thus you can beat him just with your own Twin-Head without any equips, especially as the Sea field powers it up. Martis uses powerful fiends and spellcasters for his main attacking force, that while still strong, do not get powered up by the Wasteland field; this results in him fielding significantly weaker monsters than what the other high mages are using against you, and leaves him reliably beaten by an unequipped Twin-Head.
In the endgame gauntlet, the second opponent (or first if you defeated Seto 2), Sebek, is much easier than the high mages you dueled and defeated, as well as easier than the opponents to come. He uses machine and beast type monsters, with the strongest being by far a Metal Zoa (which while it has 3000 attack, you have already defeated opponents fielding stronger monsters than this), and while dueling him on a yami field, which does nothing to boost his monsters. Most of his remaining monsters only have slightly more than 2000 attack, and he has no significant magic/trap cards nor equips.
Complete Monster: Heishin, the Big Bad invented for the game. An Evil Chancellor and Evil Sorcerer of Ancient Egypt, as soon as he gets the ancient power of the Millennium Items, he attacks the palace with his soldiers, killing various people (including the Pharaoh and his wife) and mortally wounding Simon Muran, the Prince's tutor. When the Prince tries to escape, he threatens to kill him if he doesn't give him the Millennium Puzzle. The Prince shatters it, and is transported inside of the puzzle to the present day. When he returns, he finds that Heishin has destroyed much of Egypt and Simon Muran dies from his injuries. After defeating Heishin's top mages, he finds Teana has been kidnapped and is having her life threatened in an attempt to lure the Prince into a trap to kill him, but this is stopped by Seto, his own henchmen, who sets her free and ends up being The Starscream. Heishin obtains the Millennium Puzzle and summons the Dark God, Darknite and commands him to destroy the world and make him a god. Darknite turns him into a card and throws him incinerates him in response. Petty, selfish, and so obsessed with power that he'd attempt to murder underage teenagers in his pursuit of it, Heishin was a truly monstrous individual.
Weevil Underwood is the second opponent the player faces in Kaiba's tournament, as well as the third mandatory opponent. While the player could coast through the early game and Rex Raptor with their starter deck, Weevil is a step up from Rex, and unless the player has a solid grasp on fusions and did some grinding to improve their deck, they are likely to get stomped by him. Once the player learns how to play and to adequately grind, Weevil will fall easily, though having provided a taste on what is to come.
Pegasus is the seventh opponent in Kaiba's tournament, who is dueled in the quarterfinals. He is a significant step up from prior opponents, with powerful magic/trap cards, good equips, monsters with 2000+ attack, and the capability to create many powerful fusions. He is also the only opponent not in the endgame to be able to see your facedown cards. He is likely to be the first roadblock in a player's progress, and if it hasn't been done already, will drive it in to the player that grinding is an absolute necessity in this game, as well as knowing exactly what you're doing when playing. Arguably That One Boss, though the opponents to come provide similar difficulty.
Ensemble Darkhorse: The Meadow Mage. He's just a mook you only see on one screen in the game, yet he's the character that's remembered and talked about the most. With his amazing card drops, including giving most people their first Meteor Black Dragon, people have fond memories of extensively dueling him and gaining the cards that allowed them to finally beat the game.
The exact monsters required for each ritual card. While the description of each ritual card gives you a hint on what is required, these hints are commonly vague, and often don't cover all three monsters needed to complete the ritual.
The possible fusions in the game. Most are simple enough to reasonably figure out on your own through some trial and error, and the fusions requiring specific monsters are intuitive (such as Black Skull Dragon), as well as can be learned from following the anime and playing the card game. Fusions can also be learned by watching what the computer fuses. The fusions requiring magic cards on the other hand...
The fact that getting a power or technical rating when winning a duel affects the card you win (getting a power ranking gives you a chance to win more powerful monster cards, while a technical rating gives you a chance to win more useful magic and trap cards). Exactly how to obtain a technical ranking instead of a power ranking is never explained by the game or its manual.
The cards you can win from each opponent. While sometimes intuitive (such as being able to obtain a Red Eyes Black Dragon from Jono 2), they are nonsensical other times (such as being able to obtain a Meteor Black Dragon from the Meadow Mage).
The fact that many cards can not be legitimately obtained in the game without unrealistic grinding to 999,999 starchips (such as Summoned Skull), or unable to be obtained at all.
The correct path to traverse the labyrinth when rescuing Teena (which is right, right, left, right). While it isn't too complicated for one to reasonably figure out on their own, there is no indication that you encounter the Labyrinth Mage if you go the wrong path instead of the right path, and there's no indication that going the wrong path brings you back to the beginning.
Nintendo Hard: Since this game was made a few years before the actual card game was released (Was Released in US shortly after Duel Monsters was Localized and following the card game as well), the game is extremely unbalanced. Additionally, the deck strength of your opponents scale rapidly once you progress past the early game, the opponents will have access to many powerful cards you'll never legitimately be able to use, and you will need to grind a lot, often to just defeat the next opponent in the story, and especially to be able to survive the endgame.
That One Boss: High Mage Kepura is the most difficult of the high mages you'll face, and is as difficult as what you'll face in the endgame, using Gate Guardian powered up by the meadow you duel him on. With an attack over 4000, it'll take just two direct attacks from it to be defeated. Even the Meteor Black Dragon alone won't gain you victory here. Seto 3 is also this, being the most difficult opponent in the game, having Blue Eyes Ultimate Dragon and nearly every other extremely powerful monster, as well as the most powerful magic, trap, and equip cards.
Unwinnable by Insanity: When trading with another player, you're not required to put up the same amount of cards the other player is trading (nor have to put up any card at all). As such, it's possible to trade all your cards in your chest, and while the game does not allow you to trade cards that are in your deck, the game does not disallow you from exiting the build deck screen with less than 40 cards in your deck. So if you were to trade without 40 cards in your deck, and traded enough cards away, you would not have enough cards left to fill out a 40 card deck. And since you can't have 40 cards in your deck, the game will not allow you to duel anyone, thus preventing you from being able to play farther and preventing you from being able to get more cards to fill a 40 card deck again. The only ways out of this are to have enough starchips from beforehand to buy enough cards to fill out a 40 card deck (which considering the inane prices, is very unlikely), or get more cards from a player in a trade. Of course, the player would have to be intentionally invoking this, as there's no reason to exit the build deck screen with an incomplete deck, nor a beneficial reason for trading away all your cards to another player without getting anything in return.