Are the highlights of Seville spread out to warrant hop-on/off bus?

Seville is extremely walkable and the historical center is largely a maze of bus-free streets, so I don't see the need for it.

Not really. The HoHo bus does give you a route into and out of Triana neighbourhood and it stops near parliament which is a good starting point into the Macarena neighbourhood. But you could accomplish this without the HoHo and it will not be useful for the central sights around the Catedral and Santa Cruz. We've used it and its okay, but with only 2 days I think you can plan something better without the HoHo. After the highlights you mention, plus touring Santa Cruz, I think a top sight would include either (or both) Casa de Pilatos or Casa de las Dueñas, both of which you can walk to from the centre, and Parque Maria Luisa (which the bus can't go into, but would take you around the park and drop off at one of the entrances).

Even if you do take the bus, I personally advise against adding the river cruise. The Sevilla skyline is not great from the river and you get a better view from the top of the "mushroom" market [Edit -] I mean Metropol Parasol, which is possibly on your walking route from the centre to the aforementioned casa and is near the worth visiting Santa Catalina church and El Rinconcillo (a bit touristy, but we're tourists so why not?).

I do not remember seeing HOHO buses. They can’t enter the areas you wish to visit in the historic areas with narrow streets. They are reachable on foot.
We also found the Seville Plaza de Toros, bull ring , interesting to visit.

thank you all for the excellent advice!

We stayed at Hotel Derby and were able to easily walk to all we wished to see in Seville. Beautiful city, my favorite in Spain.