Yeah. Lots of changes. They reduced the number of ages down to three, Antiquity, Exploration, & Modern. In each age, you play a different civ. For example, you could start Antiquity with the Romans, transition into Spain for Exploration, and finish as Mexico in Modern.
Leaders and Civs are detached, so now you can play as Benjamin Franklin of Egypt or Napoleon of Japan. Leaders stay with you the whole campaign.
Settlers create Towns now instead of Cities. Towns are like puppet cities from Civ 5 in that they act autonomously. They mainly serve to harvest and send resources to your Cities. If they grow enough in population, you can spend money to convert them into Cities. District system has been reworked. Now there’s only two types of districts, Urban and Rural. Rural districts take the place of resource improvements, since there are no more builders. Urban districts get two building slots, and from what I’ve seen some buildings do get adjacency bonuses.
There’s a new unit called Commander that lets you stack your other army units on top of it and transport them across the map. Still have to unstack your army to engage in war.

There’s more changes, but these are main ones that jumped to mind in terms of dramatically changing the feel of the game.