Keywords vs Spotlight Comments

What is the difference between keywords and spotlight comments on a file?

Well, the are separate entities. The comment field is just a blob of text. The keywords are a list of individual terms. Semantically, think of the first as a description or note and the second as a bunch of tags.

Effectually, there might not be as much of a difference. Both get indexed by Spotlight. App support for the fields is a bit confused and sporadic right now which is unfortunate.

If in doubt, use what makes sense semantically.