Thanks, that seems simple enough, it works and only takes about 8 seconds so should be good. I don't know if my interpretation of the suggestion is optimal but it got me to a solution, I just used an array as my data didn't need a keyed hash. The files are fairly basic text, less than 40,000 lines.

#!usr/bin/perl
use warnings;
use List::MoreUtils qw(any);

open my $wave,    '>', 'Wave' or die "Can't open $wave: $!";
open my $keywords,    '<', 'Agents' or die "Can't open keywords: $!";
open my $search_file, '<', 'Definitions'   or die "Can't open search f
+ile: $!";
open my $schedule, '<', 'Schedule'   or die "Can't open search file: $
+!";

@sched = <$schedule>; # read entire file into an array at the start
my $keyword_or = join '|', map {chomp;qr/\Q$_\E/} <$keywords>;
my $regex = qr|\b($keyword_or)\b|;

while (<$search_file>)
{
    while (/$regex/g)
    {
        $line = $_;
        chomp $line;
        if ( $line =~ /(SCRIPTNAME|DESCRIPTION)/ ) {
        next; 
        }
        print $wave $line;
        
        if (any { $_ =~ $line } values @sched) { # check if line we're
+ on is also in the @sched array
            print $wave " | Yes!\n";
        }
        else{
            print $wave " | No!\n";
        }

    }
}
$_->close for $wave, $keywords, $search_file, $schedule;
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