Wendell Pierce is not a trombonist. He started taking lessons when he was cast as a trombonist, so his handling of the instrument would look credible on-screen. When Antoine Batiste plays, a professional trombone player off-screen provides the actual music. In season 4, a version of this behind-the-scenes story plays out in one of Antoine's story lines, when Antoine is hired to teach a non-trombonist actor (Lanny Fox, played by Wilson Bethel) to fake playing the trombone credibly during a movie shoot.

Real New Orleans musicians or bands who appeared on the show as themselves include: Kermit Ruffins, Coco Robicheaux;, Donald Harrison Jr., Dr. John, John Boutte, Art Neville, Irma Thomas, Clarence 'Frogman' Henry, Troy 'Trombone Shorty' Andrews, the Dirty Dozen Brass Band, Galactic, and the Hot 8 Brass Band.

Elizabeth Ashley was a close friend of Tennessee Williams. She is also one of the preeminent stage interpreters of his female characters. Starting with her performance as Maggie in a 1974 Broadway revival of "Cat on a Hot Tin Roof," she has played nearly all of Williams's female leads.

Many real New Orleans and New Orleans-area restaurants, bars, and other venues have been featured on the show, including: Lil' Dizzy's Cafe, Vaughan's, Cafe Du Monde, Mosca's Restaurant, Tipitina's, Dooky Chase's Restaurant, The Rock'n'Bowl, and The Blue Nile. Janette's fictional New Orleans restaurant, Desautel's, was "played" by the real-life restaurant Patois. Storylines have also focused on the real-life New York restaurant Le Bernadin and a fictionalized version of Momofuku Ko and Ssäm Bar. Those New York-set scenes were actually filmed on a soundstage in New Orleans.

Tim Robbins became a fan of the show while he was shooting in New Orleans for Green Lantern (2011), watching it at the motel he was staying in. Impressed with the realism of Treme, Robbins contacted David Simon and eventually directed an episode.

According to David Simon, Spike Lee recommended Elizabeth Ashley because she is a true New Orleans persona.

Real chefs and/or restaurant owners who have appeared on the show as themselves include: Eric Ripert of Le Bernadin in New York, JoAnn Clevenger of Upperline, David Chang of the Momofuku restaurant group in New York, Tom Colicchio formerly of the Grammercy Tavern in New York, Wylie Dufresne of wd~50 restaurant in New York, Leah Chase of Dooky Chase's, and Donald Link of Cochon Butcher.

Agnieszka Holland directed both the first and last episode of the show.

The title of the first and the last episode are a compound, resulting in "Do You Know What It Means to Miss New Orleans", which is a famous song written by Eddie DeLange and Louis Alter, first heard in the movie New Orleans in 1947, where it was performed by Louis Armstrong and sung by Billie Holiday.

The character of Toni Bernette is loosely based on real-life lawyer Mary Howell, a long-time collaborator with the American Civil Liberties Union.

When Janette Desautel's father tastes her cooking, he praises it by saying "we are not in Huntsville any more." Kim Dickens was born and raised in Huntsville, Alabama. According to one of the First Season DVD extras, the writers decided Janette was from Huntsville so Dickens could use her everyday voice and accent in the role instead of having to adopt a New Orleans accent.

Michiel Huisman, India Ennenga and Chris Coy appeared in so few episodes in season 4 because of budget cuts.

According to a 2012 story on National Public Radio's "All Things Considered" the character of Janette Desautel is loosely based on New Orleans chef Susan Spicer, owner and is head chef at Bayona.

Davina Lambreaux crosses paths twice with Kimberly Rivers Roberts. The second time, Roberts gives her a CD with a documentary she helped making. In real life, Kimberly Rivers Roberts documented the Katrina experience on her neighborhood on video, and played an integral part on the Oscar nominated documentary Trouble in the Water (2008).

Khandi Alexander previously worked with two of her season 1 co-stars. Melissa Leo, playing her lawyer, worked with Alexander in the 1985 film Streetwalkin'. Lance E Nichols, who plays her 2nd husband, guest starred on Newsradio in 'Daydream' as the coworker Alexander's character wished she had (all her actual coworkers at the time being white).

Clarke Peters and Rob Brown, who play father and son on 'Treme' (Albert and Delmond Lambreaux respectively), have both starred in a movie with Sean Connery. Rob Brown starred with Connery in 'Finding Forrester'. Clarke Peters starred in 'Outland'.

Melissa Leo and John Goodman also co-stared in the film 'Red State'(2011)

The first regular character to appear in the first episode of seasons 1, 2, and 3 is Antoine. The first ones to appear on season 4 are Toni and Sofia.

The character of Oliver Thomas, the New Orleans politician who gives Toni's daughter Sophie an internship, is forced to resign after he admits to taking bribes. He is played by Oliver Thomas, who served as a New Orleans City Councilman from 1994 to August 2007, when he resigned his council position after pleading guilty to a federal bribery charge.