mod_rewrite is probably the easiest way to do it, and you wont clutter up the server lots of folders that take up 4k each just to hold no files.
here is a rewrite rule you can put in .htaccess
RewriteEngine On
RewriteRule (.*)$ /index.php?user=$1 [R]
if you make a folder on your site called users, (yoursite.com/users/) create a .htaccess file in that folder, and put the above code in it, now anytime someone goes to yoursite.com/users/username they are redirected to yoursite.com/index.php?user=username