This is the first Resident Evil game in the franchise where Alyson Court does not provide the voice for Claire Redfield.

Takes place between the events of Resident Evil 5 (2009) and Resident Evil 6 (2012).

At the time, the game set a new standard for use of profanity in the series. Most of the other installments had an M rating for mild language, but usually nothing worse than use of a few s-words. Resident Evil 5 (2009) and Resident Evil 6 (2012) were moderate for incidental uses of the f-word and other crude expletives. Resident Evil Revelations 2 features copious use of f-bombs, a lot of them used by a 20-year-old.

This is the second game in the series in which the active part starts with Claire Redfield waking up in and being released from a prison, after Resident Evil - Code: Veronica (2000).

In Chapter 1, after busting the locked gate to the radio tower, Barry yells "Who's the Master of Unlocking now, huh?" This is a witty callback to the original Resident Evil (1996), where Barry gave Jill Valentine a lock-pick while uttering the classic bad line "It might come in handy if you, "the master of unlocking", take it with you."

Oddly, Resident Evil: Revelations 2 was never released for the Nintendo 3DS even though that was the original platform the first Revelations was developed for and released on. Revelations 2 is available on the PlayStation 3, PlayStation 4, Xbox 360, Xbox One, PS Vita, and PC.

As the English voice recording was not done with a SAG-AFTRA approved contract, most of the American voice actors were using pseudonyms or at least similar versions of their names in order to distance themselves from their union-approved work.

This is the second game in the series to use the Uroboros virus as a plot element (first being Resident Evil 5 (2009)). However, this is the first game to analyze the effects of a successful merging, as well as using it to make B.O.W.s.

There are two endings to Revelations 2: the good (canon) ending and the bad ending. In episode 3 during Claire's section, the choice made during the boss fight with Neil decides how the game ends: if Claire is the one to deliver the killing shot, then the bad ending will take place. If Moira is the one to deliver the shot, then she will overcome her aversion to guns and aid her father Barry in the finale, leading to the good ending.

The first Resident Evil game to feature Albert Wesker's twin, Alex Wesker.

After escaping a trap early in the game, Claire will joke that she was nearly a Claire sandwich. Moira responds with annoyance, wondering if her father tells everyone that story. This is a reference to Barry's infamous "Jill sandwich" line from the original Resident Evil.

The "Only Good Guys Win Medals" trophy is a shout out to Wreck-It Ralph, a famous Disney film.

The "I Can See Undead People" trophy is a shout out to the iconic like from The Sixth Sense.

The "Routes of Future Past" trophy is a shout out to Days of Future Past, a famous Uncanny X-Men storyline.

Mistakes

If the Player is controlling one player character, the other one can fire his or her weapon but the ammunition doesn't deplete.

Timers stop during cutscenes.

Valves sometimes turn to the left to turn obstacles like flame jets off. Valves invariably are designed to close by turning right.

Natalia is capable of lifting and moving an object that Barry says would throw his back out if he moved it too far and which looks like it weighs more than her.

When Alex Wesker shoots herself in the head, she places the handgun to the side of her temple. When shooting, the blood and brain matter splashes across glass directly in front of her. There is no way this could have happened unless the gun was fired from behind her head, or she turned ninety degrees to her right.

During a New Game+, it is possible for Claire to be armed immediately, even though she was captured and put in a prison cell.

Certain weapons hold varying amounts of ammunition that shouldn't be possible.