As far as I can see, the problem isn't the tilde so much as the unescaped character just before the tilde. It's the same as your separator. If you use a slightly different syntax for the search and replace, you can do the transformation without issue.

~/perl/monks$ cat test_tilde.pl 
#!/usr/bin/perl
use warnings;
use strict;

my $test = "This is a test
of a replacement 
string, really (example.com) 
and truly."; 

print $test, "\n";

$test =~ s|example\.com|12\.23\.56\.78\/\~example|g;

print $test, "\n";
[download]

The output is:

~/perl/monks$ ./test_tilde.pl 
This is a test
of a replacement 
string, really (example.com) 
and truly.
This is a test
of a replacement 
string, really (12.23.56.78/~example) 
and truly.
[download]

---

---

Posts are HTML formatted. Put <p> </p> tags around your paragraphs. Put <code> </code> tags around your code and data!

Titles consisting of a single word are discouraged, and in most cases are disallowed outright.

Read Where should I post X? if you're not absolutely sure you're posting in the right place.

Please read these before you post! —

• How do I compose an effective node title?
• How do I post a question effectively?
• Markup in the Monastery

Posts may use any of the Perl Monks Approved HTML tags:

a, abbr, b, big, blockquote, br, caption, center, col, colgroup, dd, del, details, div, dl, dt, em, font, h1, h2, h3, h4, h5, h6, hr, i, ins, li, ol, p, pre, readmore, small, span, spoiler, strike, strong, sub, summary, sup, table, tbody, td, tfoot, th, thead, tr, tt, u, ul, wbr

You may need to use entities for some characters, as follows. (Exception: Within code tags, you can put the characters literally.)

	For:		Use:
	&		&
	<		&lt;
	>		&gt;
	[		&#91;
	]		&#93;

Link using PerlMonks shortcuts! What shortcuts can I use for linking?

See Writeup Formatting Tips and other pages linked from there for more info.