Horseshoe Bay "feels" a lot further from the airport than Tsawwassen does, probably because you have to go through Vancouver to get there, and would definitely be harder to get to in rush hour traffic. In either case, the fact that you really have to reserve a car spot (if you are taking a car), or face an hours-long wait in the summer also makes the logistics harder, so it's probably best to rent a car once on the island.

I don't see any reason to land in Vancouver, though, for the reasons stated above. Landing at Victoria airport and renting a car to Nanaimo is probably the best combination of easiest and cheapest, despite the extra connection. Next would be nonstop to Seattle, the Clipper, and renting a car in Victoria.