In Roberto's chapter, Pious says, "I am the scourge of God, appointed to chastise you, since no one knows the remedy for your iniquity except me. You are wicked, but I am more wicked than you." These words are identical to the ones spoken by the warlord Tamerlane Khan before sacking Damascus.
The family name Roivas is "Savior" spelled backwards.
If you complete Karim's level with low sanity, you get a false ending where it tells you to wait for the next Eternal Darkness game. This was a parody of Legacy of Kain: Soul Reaver, which had a similar ending.
The sanitarium Maximillian Roivas is committed in is called "The Jefferson-Coombs Sanitarium". It is named after Jeffrey Combs, who is well known for his acting roles in many Lovecraftian films, most notably the "Re-Animator" series, by Brian Yuzna.
The game has 40 unique insanity effects.