I believe the loop may be shortened to just this:

    foreach my $key (@_) {
        $hr = $hr->{$key} ||= {};
    };
[download]

I did a quick benchmark and it looks like it's also faster:

#!/usr/bin/perl -w

use strict;
use Data::Dumper;
use Benchmark qw(cmpthese);

my $hash = {};

set_hash( $hash, 42, qw(foo bar baz x y z t) );
print Dumper( $hash );

my $hash_foreach = {};
set_hash_foreach( $hash_foreach, 42, qw(foo bar baz x y z t) );
my $hash_exists = {};
set_hash_exists( $hash_exists, 42, qw(foo bar baz x y z t) );

Dumper($hash_foreach) eq Dumper($hash) or die "hash_foreach inconsiste
+nt";
Dumper($hash_exists) eq Dumper($hash) or die "hash_exists inconsistent
+";

cmpthese ( -1, {
    while => sub {
        for (1..10000) {
            set_hash( {}, 42, qw(foo bar baz x y z t) );
        };
    },
    foreach => sub {
        for (1..10000) {
            set_hash_foreach( {}, 42, qw(foo bar baz x y z t) );
        };
    },
    exists => sub {
        for (1..10000) {
            set_hash_exists( {}, 42, qw(foo bar baz x y z t) );
        };
    },
});

sub set_hash {
    my $hr = shift;
    my $val = shift;
    my $last_key = pop;
    while (@_) {
        my $key = shift;
        $hr->{$key} = {} if ! exists $hr->{$key};
        $hr = $hr->{$key};
    }
    $hr->{$last_key} = $val;
};

sub set_hash_foreach {
    my $hash = shift;
    my $value = shift;
    my $last_key = pop;

    foreach my $k (@_) {
        $hash = $hash->{$k} ||= {};
    };
    $hash->{$last_key} = $value;
};

sub set_hash_exists {
    my $hr = shift;
    my $val = shift;
    my $last_key = pop;
    foreach my $key (@_) {
        $hr->{$key} = {} if ! exists $hr->{$key};
        $hr = $hr->{$key};
    }
    $hr->{$last_key} = $val;
};
[download]

I thought exists would benefit over a ||=, but it looks like it doesn't:

$VAR1 = {
          'foo' => {
                     'bar' => {
                                'baz' => {
                                           'x' => {
                                                    'y' => {
                                                             'z' => {
                                                                      
+'t' => 42
                                                                    }
                                                           }
                                                  }
                                         }
                              }
                   }
        };
          Rate   while  exists foreach
while   21.3/s      --    -10%    -21%
exists  23.6/s     11%      --    -12%
foreach 27.0/s     27%     14%      --
[download]

Still I ++ your answer.