@rjhinkle Hi. If you’re using Windows 10 can you try following this guide first?
Also make sure you are the administrator of your own system, or at least have access to the system account password, otherwise only a few of those tips will help you when attempting to open the program.
As a last note, Pencil2D behaves as a portable application, you don’t need to install it, but Windows has made it worse for these kinds of apps to work, so make sure to review the guide particularly the steps for the antivirus, the developer mode and unblock/unzip on a system folder (i.e Program Files)