Best way to travel from Nice - Santenay?

I'm not sure that the flight from Nice to Lyon saves much time vs. the train - maybe 1 hour once you factor in airport hassles, and at a high carbon footprint. However you put it, it will take up most of day...
If you do take the train, I do not recommend Lyon Part Dieu as a destination, but Lyon Saint Exupéry. You'll have to take a shuttle or walk 12-15 minutes to get to the car rental offices, but you won't have to deal with Lyon traffic and thus you will save a bit of time on the way to Santenay.

Is there any way/ do you have any desire to spare some time for either Avignon, Aix or Lyon? They're lovely stopovers.

thank you, we will be short on time and wanting to make the most of the time we have in both Nice and Santenay where we will be with family. Seems like it's a 1hr flight vs 3.5hr train from Nice to Lyon or the other stop is a great tip if we train and seems to be less expensive to fly too but I hear you on carbon footprint. We'd be happy to do a stop on the way from Lyon to Santenay once we rent a car if there's a place or two you recommend that are easy to park near and do a quick walk about?

When I say Aix, Avignon or Lyon are good stopovers, I meant overnight stopovers. If you don't have time to spend a night there, then don't stop.
Between Lyon and Santenay... Well, if you leave from Lyon Saint Exupéry, you could spend an hour or two in Pérouges, a lovely medieval village. Tournus is also good for a quick leg-stretch, plus it is very close to the motorway junction so it does not waste much time (have a look around St Philibert church if you do stop there).