Julian Richings (who played Death) later on complained jokingly in several interviews at conventions about the shooting of the pizza parlor scene, because it had to be re-shot numerous times with both himself and Jensen Ackles having to eat more pizza with each re-take.
This marks the first episode that Bobby uses his catchphrase "Balls!".
The nursing home Sam and Dean search for Pestilence in is called "Serenity Valley". This was the name of a battle in Firefly (2002), the short lived show Mark Sheppard (Crowley) had a recurring role in. Also Ben Edlund, this episode's executive producer, was a producer on Firefly.
Many Supernatural episodes share a title with a Rock or Metal song. 'Two Minutes to Midnight' is one of these. It is the first single track from an album released by Iron Maiden in 1984. The song, the literal title of which is '2 Minutes to Midnight' refers to the closest approach to midnight ever of The Doomsday Clock in 1953.
Julian Richings played Death in at least two other roles besides Supernatural, including the Hallmark film Ms. Scrooge (1997), and the short film Dave vs Death (2011). He also played a similar role in Percy Jackson & the Olympians: The Lightning Thief (2010) as the ferryman to the Underworld.