Jennifer Aniston reconnected with her husband Justin Theroux on the set of this film. They had originally met in 2008 after being introduced by Robert Downey Jr.. As of June 2019, they are legally separated.

Despite being naked throughout the film, Joe Lo Truglio wore a prosthetic penis. Most of the cast ran up to him and touched it as a joke after showing up on set.

George's "mirror talk" was improvised by Paul Rudd.

The trailer has a clip of Paul Rudd walking into his room to find Jennifer Aniston lying on the bed with two other women. Rudd asks "What happened?" to which Aniston replies "You just missed it. It was so beautiful." This clip is not in the movie.

Jennifer Aniston and Paul Rudd previously co-starred in Friends (1994) and The Object of My Affection (1998) (in which Rudd's character also was named George). Alan Alda co-starred in the latter as well.

Jessica St. Clair plays a reporter that falls over while stomping grapes. This is a reference to a popular YouTube video in which an actual news reporter took a fall in a grape stomping competition.

This was the last film to use the late 1990s Universal logo.

When George is standing in line getting coffee at the beginning of the film, the sign behind him reads "New York Office Building (actually in Atlanta)", a site gag obviously referring to the fact that the film was wholly shot in and around Atlanta.

Jessica Alba turned down the role of Eva.

At the start of the guitar scene where George and Seth play "Two Princes" you can hear some of the others singing "Love Take Me Down to the Streets" a song written and recorded for David Wain's previous film Role Models (2008). The song is meant to sound like the Paul McCartney band Wings, and is often believed to be a Wings song as a running gag throughout Role Models.

Kathy says a mispronounced line in Swedish ("God afton") and says that she studied economics in Stockholm. Malin Akerman, who plays Eva, is Swedish and born in Stockholm.

Fred Armisen was originally cast as Wayne Davidson before Joe Lo Truglio signed on.

In an episode of Friends (1994), Jennifer Aniston says of Ross "If I squint, he looks like Alan Alda". She has starred with Alda in two movies, including this one.

During the scene at Elysium where everyone is sitting around the 'truth circle' and George is given a bowl of Ayahuasca tea to drink, he smells it and passes it to Linda saying that the tea "smells like Willie Nelson's braids". Willie Nelson was the name of Paul Rudd's character's pet dog in the movie Our Idiot Brother (2011) which, incidentally besides Paul Rudd also starred Kathryn Hahn.

The fourth collaboration between Paul Rudd and Kathryn Hahn. They previously worked together in Anchorman: The Legend of Ron Burgundy (2004), How Do You Know (2010), and Our Idiot Brother (2011). They have also worked together on Parks and Recreation

Jennifer Aniston and Katherine Hahn also appeared in We're The Millers (2013).

Jennifer Aniston's character in this movie had written a children's book. She had also written a children's book in Along Came Polly.

This will be the third time Paul Rudd plays a character named George. He previously played a George in The Object of My Affection (1998) and How Do You Know? (2010)

David Wain: [Jim Stansel] The name "Jim Stansel" that appears on the business card is in every David Wain movie.