A found a few problems.

According to you VB snippet, ",user" is appended to the first string; it's not a seperate argument.
Win32::OLE->GetObject("WinNT://wsi/$username", "user");
should be
Win32::OLE->GetObject("WinNT://wsi/$username,user");

Don't forget to double backslashes in hard-coded strings.
"\\server\homeshare"
should be
"\\\\server\\homeshare"

HomeDirectory is proably a property, not a method, so
$User->HomeDirectory("\\server\homeshare");
should be
$User->{HomeDirectory} = "\\\\server\\homeshare";

Unfortunately, that doesn't seem to be enough.

use strict;
use warnings;

use Win32::OLE ();

my $user_name = 'Administrator';

my $user = Win32::OLE->GetObject("WinNT://wsi/$user_name,user")
or die("\$user is undef\n");  # <---- dies here

print($User->{HomeDirectory}, "\n");

# $user->{HomeDirectory} = "\\\\server\\homeshare";
# $user->SetInfo;
[download]

But that's probably cause I'm not running a compatible platform. MSDN says this interface is only available on Windows 2000 Server and Windows Server 2003, which I don't have.