Toad 16.0, 16.1, or 16.2?
Also, do you know that you don't have to select anything before running as script? You can just run as script.
I tried to reproduce this but is working fine for me.
Maybe related to this? F5 not working after multiple F9s across multiple editors
Once it happens, does it continue happening until you restart? What do you do to get it working again? Does it only happen when a comment is included in the script?
When it starts happening, one test you could to is turn on Spool SQL to see if it tries to execute any SQL at all.