One of the most effective ways I've seen to shake things up in a new campaign is to change the available classes.
Most of the time players come to expect a certain mixes depending of course on system.
By changing this mix you can not only change the flavor of the world but how players interact with it. A couple of published examples, Monte Cook's Arcane Unearthed is recognizable as D20 and outisde of spell casting has a small learning curve but its mix of Warmains. Unfettered, Magisters and Greenbonds provide a meaningfully different game than the standard Fighter, Rogue, Wizard, Cleric mix.
In settings like Age of Mortals for Dragonlance with the addition and emphasis on new classes like Master, Noble and Mariner can shake up a game and take it in interesting new directions.
The same thing can happen when you change classes in older games, game with Fighters, Clerics, Magic User, Thief ,Elf, Dwarf and Halfling is quite different than one with Swordmaster, White Mage,Black Mage, Rogue and Sidhe ( Elves with Illusionist magic), Dwarf Runecasters and Halfling Thornwalkers even if the mix of spells and abilities is pretty similar to a standard game.
Now some caution is advised. New stuff needs to be balanced, , in some games niches need to be filled and of course it all needs to be fun and interesting for player and GM.
If you can meet that hurdle, try changing things up. I think you'll like it.
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