If we are talking about Windows here, it will "flag" any unsigned exe downloaded from the internet, as potentially malicious.
That being said, there are ways around it.
You can wrap it in an installer. and sign yourself as a developer. Or try to make your players to use itch launcher as it voids this issue.
But if some antivirus software is flagging it as malware that is a completely different animal and I do not know much about it.