Uber is going to be your friend in San Diego, mostly just because it's so big. I'd look at the Gaslamp Quarter or downtown - lots of hotel choices, though they will be a bit more expensive because they're closer to stuff. You may also like the Old Town area - more historic stuff. You can take the train to San Ysidro and jump over the border to Tijuana, but it's pretty touristy. Probably better uses of time in the area.
@Gee Wally to piggy back off of the post above...
Definitely Uber/Lyft. There's a million of them around, and you can get from one end of the city to the other for $10-15 max.
I'll also second Old Town area. A lot history in such a small area, plenty of resturants and some shops around.
Also, definitely check out Gaslamp District. There's plenty of places to eat in Gaslamp. I'd recommend SearSucker. Just great food, and a nice atmosphere. Directly across the street is a place called Barley Mash, which is nice for a quick beer and bite, but with food a bit more upscale than regular bar food.
Depending on when you're planning on heading out there, if you're into baseball, I'd recommend checking out Petco regardless of who the Padres are playing. It's an awesome park.
I know you mentioned your wife wanting to see the Zoo, definitely do it. It's huge, and you easily could spend the whole day there. Close by is Balboa Park, which has some museums, the rose gardens on the far end, food trucks on Fridays in the spring/summer. My wife has a friend that works at the open air bar there as well. Say hi for us
USS Midway is absolutely worth seeing as well. It's similar to all the other floating museums like the Intrepid in NYC, but given the history of that ship, there's something more to it personally. They have guest speakers from time to time, and the last time we were there, they had a WWII vet speaking which was great.
If you rent a car at all, it's worth just taking a quick ride to La Jolla and riding around. There are some awesome houses, and some amazing views, plus plenty of small one off shops. Only worth doing if you have your own car IMO.
Definitely take a ride to Coronado. Also some amazing views, and it's a great beach and area in general. Plus there's the history with the Coronado Hotel. You can also Uber/Lyft here and not feel like you're stuck there.
I'm sure my wife has other suggestions as she lived there for 3 years, but off the top of my head, this is what I came up with.
EDIT: One thing I forgot. Definitely get out on a pier and see the sunset over the Pacific, especially if you've never seen it before. It's awesome.
