My wife and I live in a two story, 4500 sq. ft. home built in 1990. Our master and office is down stairs along with the kitchen, living area, dining room, etc. Upstairs is 3 bedrooms, two baths, and a family room. They are on two separate heating a cooling systems. We can go weeks or months without using the upstairs until we have visitors. My question is, is it more efficient to completely shut the upstairs off or should we run the unit upstairs, albeit at a higher temp than downstairs?

I keep upstairs shut down here at the ranch, ceiling fans on to circulate.

ours is a bit different duct system but same principle, shut all doors etc. in the upstairs and if you can program your thermostat set it to just turn on the fan at night for 2-3 hrs.

how I do it here anyway.

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B+

A huge electric bill.

I’ve noticed in the summer if we don’t keep the upstairs at a decent temp, then it makes it hard to keep the temp downstairs where we want.

That was what I was trying to get at. If we don’t run the upstairs, it will reach mid to high 80’s on some of these hot days. I may try setting the thermostat at 80 upstairs and see what it does for the downstairs.

Ours is in use everyday, since the kids rooms are up there. In the winter it flips, and we barely have to run the heater at all upstairs.

We used to not use our upstairs. I’d keep it 5°warmer than downstairs in the summer. It made it to where the downstairs would stay on the temp we set it at. I figure something similar would be your case.

My issue these days is that we do use the upstairs and can’t get it to stay cool. We need a bigger ac unit apparently.

Simple science: warm air rises, cool air falls.

Sounds like my situation. Kids are gone and we don't need all that house but we don't want to downsize because we would have to pack to move and we have too much sh-t to go through that hassle.

To answer your question, my downstairs unit is a two-stage unit so I don't run my upstairs unit. If it gets warmer than the set point, the 2nd stage kicks in and quickly cools it down.

Here is the funny part - my in-laws were coming to visit in May so my wife wanted the upstairs unit to be replaced to the tune of $7,500.dollars. They got here and the MIL's knee was hurting so they stayed in the master bedroom and never made it upstairs. So far nobody has stayed in any of the 3 bedrooms upstairs even though it has a bada--, brand new AC unit. BTW - I made her pay for the new unit out of her budget!!!

Yes same situation to most here. Live in a 5000 sq ft house, has 2 units (1 for upstairs, 1 downstairs and minisplits to all the rooms in the basement). Mini splits have never been run but going to put a gym in one of the rooms downstairs and bet I use it then. Otherwise never used a mini-split to date. The Upstairs works hard in the summer but the downstairs unit barely runs if I keep the upstairs at a decent temp (usually around 75). I will say this, I had a guy come and evaluate the insulation in my attic and he says its terrible. Quoted me 15" spray in new insulation and seal up all cracks and crevices in the attic for $6,000. I am having a bunch of landscaping and a wrap around concrete porch done but as soon as I recoup the money, I am going to have this done. Bet it cuts down on the bill a little and gains me a few years extra life on the HVAC system upstairs.

There's a fairly simple way to figure out the cost. Check your meter reading on a certain date and time, run one a/c unit for a certain period of time and recheck the meter readings, do same process again but this time running both units the same amount of time. Once you have your numbers, compare and see which way costs more to run.
Even if running both units cost a bit more, you may find it's going to be an acceptable amount for the comfort.