Painfully slow mac mini - tried so many things - what now?

I suggest running an EtreCheck report and posting it so we can assist you with finding any potential issues that may be causing the slow performance.

Ref: Using EtreCheck to Troubleshoot Potential Mac Issues - ASC

The Load Cycle Count is past the official lifetime value and could be causing problems when the drive is being accessed. Just because the Load Cycle Count is past its lifetime value does not mean the drive is necessarily bad, but I've personally seen drives have issues once this point has been reached. Since there are no Reallocated Sectors or Uncorrectable Errors the drive shouldn't be causing issues when booting externally unless the drive is being accessed during use. It is possible macOS will trigger communication with the internal drive when performs disk I/O especially when checking available devices. Spotlight might even be indexing the drive and slowing your performance especially when booted from an external drive.

You listed an "External SSD" as your boot drive in the second DriveDX report, but this drive is actually a 5,400rpm hard drive. I'm not sure where DriveDX gets the read/write speed, but the speed is even worse than your internal drive. While the external drive is connected via USB 3.1 and has a SATA 6Gb/s it should be faster. Again, I'm not sure how DriveDX derives this value.

I think your problem as shown in these reports is related to drive issues. Try running BlackMagic Disk Speed Test on both drives. I would boot each drive and run the test on both drives so you can see how much of an impact running the test from the booted drive has on performance. If you actually have an USB SSD, then it should be able to achieve 400-500MB/s when connected via USB3 and SATA3 connection. Hard drives can be anywhere from 70MB/s to 150MB/s at best on a SATA 3 or USB 3 connections.

Thanks for posting your EtreCheck report. Here are some things that stand out for me:

1. Your mini only has 4 GB of RAM & only a 500 GB mechanical hard drive. Both of these will cause poor overall performance.
2. Using a Cloud-based backup will slow performance when running.
3. The read/write speeds of that mechanical drive are dismal.
4. Without allowing EtreCheck "Full Drive Access" or running it under a user account without Administrator privileges, it only provides a limited report.

I don't use DriveDX, so I'll let the HWTech respond to those findings.

Run DriveDX to check the health of your hard drive. If DriveDX shows the drive as healthy, then post a screenshot of all the "Health Indicators" as they may provide clues. Apple's diagnostics won't detect many drive failures and these "Health Indicators" are a very good way of judging a drive's health. If the drive is failing, then it can still cause system slowdowns even if the OS is on a USB3 connected SSD. Unfortunately Apple and even many independent techs don't know to check these attributes.

4GBs of RAM is not very much and can be contributing to the problem especially if memory is being swapped out to the hard drive. Even if the hard drive is healthy you may want to consider replacing the hard drive with an SSD.

Does the performance of the internal HD affect me if I am booting off the external SSD and keeping all my files there? I don't interact with the HD at all, but maybe the system does without me knowing it?

It will depend on how you have this SSD connected to your mini. Regardless, boot up and running times should be affected since it will have to go through a USB 3.0 or Thunderbolt 2 port, as opposed to, the PCI interface that the internal drive uses.

So, you are correct that this internal drive is not the sole source of the issue, but I was just trying to make you aware it could be if you decided to boot up with it.

I'll wait for the next report run to see if I can find anything else that could be the cause.

Per chance do you use any type of anti-virus or cleaner apps?