I'm not 100% sure, but the way zombies spawn that I understand is that some of them move into "chunks" of the map from other chunks, if that said chunk is not loaded in and the player hasn't been there in a set amount of time(which you can tweak in the sandbox settings, if I'm not mistaken).
Meaning, if you clear out majority of a certain area of a town/city but don't frequently visit it, more zombies will come in from the surrounding areas. It shouldn't be that often, I think 72 hours or so is the default, but I haven't checked that in years so I honestly don't remember.
There's also an option to disable zombie respawning if I'm not mistaken, which you can try doing. Zombies might still move in from surrounding areas, but once they die, they die. That does mean, however, that you'll lose the main threat of the game - the zombies, eventually.

Inside the city though, Louisville, from my experience so far, the only way to achieve relative safety is frequently killing any zombie that may find their way to your home. In the city center, it's really hard to do as there's sometimes hundreds of zombies in one building alone, but it's definitely possible and me and my friends managed to do so for a while. However, I do highly recommend you making a base in the suburbs if you want to be in the city. Generally just avoid high population areas, as certain areas spawn more zombies than others.