I'm looking for some general help here.

I do have TimeShift installed per the advice of a Linux user on another forum, and I believe it's working well.

From what I gather, TimeShift is only backing up - as I have it configured - the system 'state' to the 3TB drive.

What I'm wondering, aside from /home and /etc and /opt (some programs live in /opt and I've come to the understanding that backing up /etc is a good course of action), what else should I be backing up, and what's the best method to backup automatically?

And if I had a real disaster; say hard drive failure, I think the most reasonable and quickest bounce-back would be to have 'image' copies of my system drive, but I've been told that it's not really that easy (CloneZilla for example must be run outside of the OS, is there another way?) and not really a reasonable way to backup my Linux box.

Instead I've been told to simply back up my user data (don't know where it is aside from the /home /opt and /etc dirs?) and nuke from orbit (format and reinstall from ISO)...

What I'm most comforable with has been image backups and deduped incrementals coming from an IT role with Windows boxes.

Any suggestions on wrapping my head around this and coming up with a game plan?

I also have a few VirtualBox VMs on this Linux box that I'd like to have backed up, and I know the images are quite large. If there's a way to have those backed up regularly, automatically, that would be quite useful.

Tyvm

For automatic user data backup to a second disk on my PC, I find to be excellent. It runs on a automated daily basis to create differential backups in tar.gz form. This means that even if you should the ability to run the restore program you can still access your backups directly.
Try to exclude data held in cache files.

You should also backup some of /var

It depends on how much effort you're willing to undertake if you do have a crash. I'm firmly in the camp of "Backup all your data." Now, anything that is known to be temporary (contents of /tmp, /var/tmp, ...) can be omitted, and anything in a cache directory can be omitted since it is "just a cache" and will be automatically regenerated or reloaded if needed. Also, directories that are virtual filesystems (/proc, /sys, /dev, .gvfs) do not exist on disk and should not be backed up. I've got a few other things that I specifically exclude (thumbnails, Trash, lock files created by running processes, ...), but everything else gets backed up.

Once I have a backup scheme in place, I run a test by replacing my disk drive with a blank one and seeing what it would take to do a bare metal recovery from just my backup. That can be quite illuminating.

I'm with rknichols in the "Backup all your data" camp. Linux is a lot better than Windows at working when restored from a backup taken while the system is running.

Your VB VMs: are they running or shut down when you want to back them up. If they are running, which OS are they running?