Mac Mini with an external USB SSD and syncing with OneDrive (or iCloud). Is it possible?

When you install One Drive on the Mac, there will be a step that will state the location of the One Drive folder at which point you can change the location. Note that this will be the only time you will be able to set this location and if you want to change it in the future you would need to un-install and re-install One Drive to change it.

Personally, I use One Drive on a limited basis for sharing only those files that need to be used between Macs and PCs and I do not use any cloud storage, not even iCloud, for any purpose other than that.

iCloud files however are stored is a special location in your users library folder on the main drive and to my knowledge cannot be relocated. Also, depending on what your other devices are, you will only be able to access those files through the iCloud website through a browser. However, if you have an iPhone or iPad they will be available through the Files app on those devices.

I believe that there is a way to relocate the entire "home" directory and all its contents to an external but I don't know how that is done or how reliable it will be. However, there is nothing stoping you from just saving files on the external drive and creating your own "custom" home file structure. As a matter of fact, I keep almost all my data on an external including music, video, and photo libraries and all my other documents and project files. The only thing that is on my internal drive is the OS, apps, and user settings, caches, and other data that the apps deem necessary to keep on the internal drive.

Phil5556 wrote:

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What about if there were two users that had their own USB drive each? Can they each move their OneDrive folders?

Please see:

Install OneDrive on an external drive - MS Support

As long as you set up each user with their own, separate computer login account they can configure their own access to their OneDrive data.

Mac user accounts are independent of others and secured with their own password and file access permissions. Applications and settings will be configured specifically for each user.