Baldur's Gate 3 is full of challenges. Sometimes, you'll have trouble trying to solve certain puzzles and other times, you will have trouble figuring out the best course of action for a certain decision that must be made.
Another thing you will need to do is face some pretty big opponents that can be extremely tricky to deal with. While a lot of battles are challenging, here are the most challenging ones in the entire game.
10 True Soul Nere
If you take the Underdark route to the Shadow-Cursed Lands during Act 1, you will come across an area known as Grymforge. Here, you will meet some Gnomes who are being terrorized by someone known as True Soul Nere. Once you meet him, if you want to save the Gnomes, you'll need to fight him.
What makes this part so difficult is that, depending on how you play your cards, you could potentially be taking on all the people in this area. Most of the workers in Grymforge will side with Nere, and you'll need to kill them all at once.
9 Ketheric Thorm
Ketheric Thorm is the main antagonist of Act 2. Once you reach the Shadow-Cursed Lands, you will learn that Ketheric is leading an army of Absolute cultists in the region. The Act culminates with a giant battle against the villain.
This battle is extremely difficult for a number of reasons. For starters, you will need to face him once, and then he will disappear into a Mind Flayer colony. You'll then need to follow him into the colony and face him twice. Since he is the Chosen of the god of death, he is pretty hard to kill.
8 Myconid Sovereign
This is another battle you will only find if you go to the Underdark. While you are down there, you will be given the opportunity to either side with Sovereign Glut (a Myconid without a colony) or Myconid Sovereign (the leader of the colony in the Underdark). If you decide to go against the Underdark leader, you'll need to face Myconid Sovereign.
This battle is so difficult because if you go against the colony's leader, the entire colony will attack you. This means that you will face everyone in the colony. There will not be a single person who takes your side. This can make this task too difficult.
7 Auntie Ethel
While exploring the Underdark, you may come across someone known as Auntie Ethel. She is an older lady who is holding a woman hostage. If you try to save the woman, Auntie Ethel turns into a hag and will attack you.
What makes this battle difficult is that Auntie Ethel will clone herself. While you can easily use a Wizard or Warlock to AOE her clones, this strategy isn't known by everyone. Some players attack the clones head-on, making it extremely difficult.
6 Bernard
Yet another boss in the Underdark is Bernard. While you are exploring in the Underdark, you may come across an Arcane Tower. This tower is guarded by a construct known as Bernard. Doing his job, Bernard will attack you if you find him.
What makes this battle so difficult is that, once again, you will have a ton of enemies to face. The Arcane Tower is well-guarded, so anytime you enter it, the guards will be waiting to attack. You want to make sure that you're ready to face them all.
5 Lord Gortash
Just like Ketheric, Lord Gortash is one of the main villains in the game. He is one of the Chosen that is controlling the Elder Brain. If you want to face the Elder Brain, you will need to kill Lord Gortash and take his Netherstone.
This battle is so difficult because Lord Gortash is a strong enemy. He also has quite a few friends who will join the fight against you, making it extremely difficult to be able to defeat him. Considering he is one of the last bosses, it makes sense he's on this list.
4 Githyanki Patrol
During Lae'zel's companion quest, she will ask you to find the Githyank Creche. During this quest, you will run into the Githyanki Patrol. While you are able to pass an Ability Check to avoid this conflict, it can be difficult.
What makes this so hard is that the Githyanki are extremely strong. They are at a higher level than the player and have the extra attack that certain Classes gain once they reach level 5. This will make the battle even harder.
3 Raphael
Raphael will appear to you once you have defeated the Goblin Camp. He will offer you his help in exchange for your soul. If you do this, you can enter his house to steal your deal. If you refuse, you can break into his house to steal the 
Orphic Hammer.
What makes this battle so difficult is that Raphael will be joined by several different enemies. Most enemies, once you defeat them, will spawn in as something else. Meaning you will need to defeat them twice.
2 Orin The Red
Orin is the final of the Chosen trio that controls the Elder Brain. Soon after arriving to Baldur's Gate, Orin will kidnap one of your companions from your camp. The only way you can save them is if you attack Lord Gortash and kill him before coming to her.
Orin, unlike her counterparts, Orin's battle can be a solo battle (without any companions) if you chose the Dark Urge Origin. This can make the battle extremely challenging. If you aren't the Dark Urge, you and your party will still have your work cut out for you.
1 Shadowheart's House Of Grief Battle
At the end of Shadowheart's companion quest, you will need to enter into the House of Grief. Here, you will be tasked with killing the worshipers of Shar who want to kill Shadowheart for betraying their goddess.
What makes this so difficult is that there are so many of them who will attack you. You will also have to deal with healers, archers, DPS, and tanks. This makes the battle one of the most difficult ones in the entire game.