Well, the problem would be that the hard drive would likely have to have a bootable operating system, as many of Garmin's mapsource settings would be in the OS'es registry.
Unfortunately, it would be very difficult to create a bootable OS that can accomodate the different types of hardware you'll encounter on your travels.. It's relatively straightforward to do it in Linux, but of course, MapSource doesn't work on Linux.
So, unless you can figure a way creating a bootable hardware-generic version of windows XP/2000 it's probaby a stretch.. Alternatively, research if MapSource works on Linux in Wine or Crossover (windows emulators) and focus on creating a USB bootable version of Linux with MapSource installed via an emulator...
One final option would be to install MapSource to the external hard-drive, capturing the registry changes while this is being installed, and saving a replica of these to a REG file. You could then hook up the USB HD to another PC, and apply the same registry changes to the new PC (which the owner might not be too happy about!). You might also have to fiddle around with drive letters in the registry settings (depending on which letter gets allocated to the USB HD). This of course depends on Garmin not having hidden non-registry files/settings, or custom drivers during boot (such as support for the GPSr as a USB device).
None of the options are very straightforward.. I might try and play around with the third one and see if I can get it working..