During Act 1, you'll have the option to let tadpoles you find burrow into your brain and give you powers that are otherwise unavilable. You'll continue to find these throughout the game, and can give them to companions too. Some of these powers are pretty great, and there's no immediate disadvantage to doing this. For some endings (I think just evil ones, but not 100% sure), and assuming you're not a mind flayer already, then using these for your main character means you may have to pass a relatively hard Constitution check or turn into a mind flayer yourself.
It may seem justified tough love to help Mayrina face reality after the nighthag encounter. But it also chops off the rest of her story. Surprisingly, turning her dead husband into a zombie and letting her leave with him turns out to lead to a very positive eventual ending.
During Act 2, at the Last Light Inn, you'll be attacked by an enemy trying to kidnap an NPC named Isobel. Whether you save her or not affects a LOT of things. If she's saved, the Inn remains as a safe harbor in the otherwise-hostile Act 2 area. And she can become a camp follower (not a companion that can join your party, but someone that hangs out at your camp that you can interact with). Also, the dialog and outcomes for some significant NPCs in Act 2 is affected. If she's taken, you don't get her back. And everyone at the Inn becomes hostile and you have to kill them. Notably, this includes the blacksmith that can help Karlach with her overheating engine. This has permanent consequences for Karlach's endgame outcome. Not necessarily negative ones - she can still get both tragic and hopeful endings - but different ones than if the blacksmith lives (and you do certain other things).
At the beginning of Act 3, you'll have the option to become a part-mind-flayer. And to confince your companions to do so. There's a significant visual effect to your appearance (and your companion's). However, there's a mod you can install via the official in-game mod installer that will remove that effect. There are a lot of benefits to accepting the partial transformation, but my favorite was a permanent Fly ability, which I used constantly in Act 3. You can definitely finish the game without doing it, though.
Act 3 is REALLY LONG and there's a LOT going on. When you reach Baldur's Gate, it may feel like the story is about to go into fast mode towards a conclusion. It isn't. Take your time because there are many interesting things going on other than the main plot. The conclusion to Shadowheart's companion quest is pretty far in, no matter how much she says she thinks it is close.
It mostly doesn't matter what order you finish the main quests in for Act 3. The following made a lot of narrative sense to me, and also let me finish most of the side quests and explore most of the city before focusing on the endgame:
- Mystic Carrion / Artist
- Orin
- Ansur (the dragon)
- House of Hope (Raphel's, optional)
- Iron Throne
- Steel Foundry
- Wyrmrock Fortress / Gortash
Other orders would be fine too, but I'd advise leaving the Iron Throne and Steel Foundry for last. Deferring Orin until after the city is fully explored and the Mystic Carrion questline is done does mean that you don't get Orin's victim back for a long time. So if in your playthrough she kidnaps someone you want to recover more quickly, you might rush straight to that without finishing the miscellaneous exploration first.
For the Iron Forge, take companions with high movement speed. Equip gear and/or take scrolls/potions for maximum mobility. Potions of Speed are good for exiting, but don't take them too early. You don't want to lose a turn being Lethargic. Don't loot anything, or fight any enemies that you don't have to. Gear or scrolls of Knock may be helpful for characters/companions who aren't good at Sleight of Hand. Omellum is the farthest away, but has the ability to teleport himself and one person next to him back to the exit. It can be done, really.
I liked deferring the House of Hope until after Ansur, because by then I'd learned enough about the Emperor that I felt justified in going against his wishes. If your main character really cares what the Emperor thinks about them, you might choose to completely skip the House of Hope. You'd miss out on some interesting story and good gear, but nothing essential.
At the end of Act 3, you absolutely have to have a mind flayer on your side to advance into the endgame. Even if you're planning on winning without the Netherstones (I'm looking at you, Gale). This mind flayer can be one of:
- You (if you volunteer to turn into one)
- The Emperor
- Karlach
- Orpheus (if you free him)
Who you choose is up to you. But be aware that there's no going back. If you, Karlach, or Orpheus turn into a mind flayer, then that's what you are. You'll still retain your personality, inventory, and abilities, but your visual appearance will permanently change.
For Karlach to turn into the mind flayer, you must have her in the party, which means she has to be with you when you take the little boat to the brain. Before going past the point of no return, the game will give you a prompt that you will no longer be able to change your part or return to camp, and an opportunity to step back until you're ready. So you can't miss it.