You did not mention which output you are generating. DId you try with a new project with just 2 topics, and adding a popup in the first topic and see if your issue persists or not.
I am generating webhelp. This problem seems to be limited to this one project. A reinstall wasn't helpful either..
The popup functionality depends on the ehlpdhtm.js file. Years ago I had a large project where popups broke in topics that were heavily buried in a deep folder structure. I managed to make them work by amending the path to the js file so it was shorter. This also meant I had to copy the js file to the folder where the popups were broken.
Helpful and Handy Links
I've come across a similar thing to Rick. It's a good idea to make sure folder structure is as simple as possible. Personally I only use one level of folders within a project.