The very first time you start EndNote, you will get a welcome screen. You can close this.
Closing the welcome screen will give you a blank grey window. Don't panic! This is normal.
From the File menu, select New. Give your file a name and save it.
This will give you a new empty database that EndNote calls a "library".
Choose a location on your hard disk that you are unlikely to change (e.g. in the Documents folder, possibly in a subfolder e.g. create a subfolder for Research).
Do NOT use folders synced or proxied with online systems (e.g. do NOT use Dropbox, Google Drive, OneDrive, iCloud, etc, as the working folder for your EndNote library).
(The default name of "My EndNote Library" is fine, but this is the default name for any new library, so renaming it to something like MyResearch or MyThesis is both more unique and decreases the chances of it being overwritten.)
There are 5 main areas that you will be working with: