The show was advertised by Comedy Central as the first 'animated reality TV series,' parodying house-based reality shows, though the reality show premise was largely dropped in later episodes.

Nat Faxon was originally cast as Xandir but was fired after the first table read because the network felt his portrayal was too stereotypically gay; Jack Plotnick was cast instead because he could play a gay character without relying on stereotypical mannerisms like a gay lisp.

Several cast members had prior connections to the creators: Jack Plotnick had worked with Jeser and Silverstein on Action, while Adam Carolla and Abbey McBride had worked with them on The Man Show; guest stars Sarah Silverman and Jimmy Kimmel also came from earlier Jeser/Silverstein projects.

Tara Strong and James Arnold Taylor had previously voiced characters together in the animated series Mutant League and the video game Final Fantasy X before joining Drawn Together.

Much of the animation was produced at Rough Draft Studios' facilities in South Korea, and a running gag in 'The Drawn Together Clip Show' jokes about listing all the Korean children who supposedly died animating the series.

The direct-to-video finale film, The Drawn Together Movie: The Movie!, was animated entirely in Flash due to budget cuts, unlike the series' usual digital ink-and-paint style.

Characters have inconsistent finger counts depending on their animation style parody: Wooldoor and Toot have four fingers per hand while Clara, Foxxy, Hero and Xandir have five, though promotional art often incorrectly gives Toot and Wooldoor five fingers.

The song 'Time of My Life' from the episode 'Dirty Pranking No. 2' had to be removed from the Season One DVD due to copyright concerns, and the show mocked this situation in the lyrics of its replacement song.

The pilot episode 'Hot Tub' received an F rating from Entertainment Weekly, which inspired a season-two episode subplot where the housemates seek revenge for the bad review, and that episode also received an F from the magazine.

The show's original tagline, 'Find out what happens when cartoon characters stop being polite... and start making out in hot tubs,' parodied The Real World's famous tagline, referencing the pilot's hot tub kiss between Clara and Foxxy, which became one of the show's defining promotional images.