As with all things here, it depends on when you're leaving. If you are motivated and get up bright and early on a weekend (like, say, on the road by 8), it would be under 2 hours from La Mesa (maybe a little more if you don't drive like me). That can easily inflate to 4 hours if you go during rush hour. Moderate traffic, say on a weekend afternoon, I'd say maybe 2 1/2 to 3 hours.
In addition to the Zoo, there's the Wild Animal Park. There's old town. Downtown makes for a nice day. It's right by the water where you can get tours of old merchant sailing ships.
Forgot to add...it's totally doable in a day. The drive back at night will be a breeze.
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