ZZ Top has been doing that in the studio since Esther was a pup. An MXR flanger on the vocals was one of the hooks on many of their 80's hits. "I'm Bad, I'm Nationwide" is a prime example. It's a matter of level matching as you suggest. Many mix consoles have a pretty hot "send" signal on their insert jacks, which you can easily cut down with a resistor voltage divider. Without this it's easy to crush the FX boxes' input circuit. The tricky part is boosting signal back up from guitar to line level. All it takes is a simple preamp, and it doesn't hurt to have a volume control on it. At one time there were studio gadget boxes sold to do exactly this. One from the 70's was stereo, called the "Headroom Horseman." They were made in North Tarrytown NY, which has since changed its name to Sleepy Hollow, for those who get the literary reference. In any case it was just a couple of op amps, a couple resistors and a power supply. You could devise your own, or find the Horseman's schematic, maybe use more modern low noise hi bandwidth op amps.
We can always stand to hear some ZZ Top:
In more recent times Saint Vincent has been doing that sort of thing in live performance. She has one mic set up normal, and another that's passed thru some sort of chorus. What's going on here as far as signal conditioning / level matching is anybody's guess. I've put this video up once before, it's a hoot, enjoy!