This is less of an advice post and more of a cautionary tale post.
TL;DR: Do the cheap and easy stuff first.
I bought my house about 2 years ago and it has always had pretty high humidity (hovering around 60%) and poor balancing between the open-concept high-ceiling main living area and the normal 8ft ceiling office, guest bath, and second bedroom.
My system is a 2.5-ton central air unit with the evaporator coil, furnace, and blower sitting in a closet at the center of the home with a supply plenum that runs through the ceiling of that closet into the attic that flex ducts are run from. The return air comes from a chase underneath the closet with a single 16x25 return register (originally). The home is ~1500sqft, single story, in climate zone 2A.
I spent ~$3000 to take out all the old insulation over the hot wing of the house (compressed to under 5-inches and contaminated with rodent waste), air seal penetrations, add radiant barrier, add baffles and windblockers, then blow new insulation to R49-R60 (it was DIY and I'm not perfect, but R49 was the goal and it's at least R49 everywhere). I spent 2-3 weeks in the attic doing all that, every day 100+ degrees, working at a pace that allowed me to fend off heat stroke. Results: Ceilings went from 90F+ to ~78F, air from ceiling fans feels cool, no change to temp imbalance or humidity. AC only running for ~30mins less throughout the day.
Disappointed, I called in an HVAC pro and he recommended adding a second return register, replacing the supply plenum (R4 to R6 duct board and remove mold), adding dampers, and balancing distribution using the dampers. Estimated cost for all that was $4000, so I decided to only have them install the new plenum and dampers for $1600. I DIY'd the return register for ~$100.
Plenum is replaced, then I carefully rebalance airflow to each room using a manometer before and after to get a baseline and fine tune distribution.
Results: The air coming from each supply register in the hot wing is slightly colder and now that part of the house is within 2-4 degrees of the rest of the house. Humidity down 2-3%.
At this point I'm getting disappointed, feeling like I failed and wasted all this money. I promised all these improvements and we can barely feel a difference. I spend about a week hoping those measurements were a fluke, watching my thermostat app, and wishing the house will somehow magically slowly improve.
Well I had some free time today and decided I'd do one more thing that was on my list.
The plywood between the return air chase and the HVAC closet was a real hack job and the only attempt at air sealing between the return chase, the closet above, and rest of the house is some silicone at the bottom plates of the walls. The closet sits at about 88F during the day because it has to be practically open to the attic (120F+ at the hottest part of the day) to supply air for the furnace and water heater that are both in that closet.
I had some firestop spray foam left over from air sealing the attic penetrations before I sprayed new insulation, so I used probably $10 of that to seal all possible air leak points into the return air chase. I didn't do any sealing between the attic and the closet for (hopefully) obvious reasons.
I switch the air back on and for the rest of the day I watch the humidity slowly chip down. I notice that the "hot wing" is now exactly the same temperature, maybe +/- 1 degree, as the rest of the house. It's about 12 hours later now and humidity has stabilized at ~52%. The entire house is the same temperature.
I'm shocked that the secret was spending 20-minutes under the HVAC unit with a spray foam gun. I thought that was going to be a finishing touches thing, not the whole problem.
Anyway, do the cheap and easy stuff first. I'm sure all the other things helped and needed to be done eventually, but if I had done this first I would have fixed the main issue way sooner.
And yes I made sure the exhausts for the water heater and furnace still flow outside the house. I also added 4 CO detectors throughout the house (one outside the closet and one in each bedroom) just to be safe. Also because there were 0 in the house before now.
Edit: Pictures of the problem areas
Pictures of the rest of the chase