Desmond is only in the pilot, but he was popular enough that fans have been asking for him to appear again. This is due to his suicidal nature really setting the show's standard for ridiculously dark humor and being played by Mike Stoklasa channeling his Mr. Plinkett voice.
Jeremy, whose total screen time amounts to less than 30 seconds, is seen as one of the funniest gag characters on the show.
DJ Spitz is considered to be one of the funniest characters in the show, being quoted a lot and having lots of fanart. This is helped by his L.A. "Cholo" appearance and behavior.
Charlie's redheaded girlfriend has exactly one sentence of dialogue, and yet has been the source of lots of fan attention and requests for her to show up in Season 2.
The grease puddle from the Salty's episode gained a small fanbase after Zach and Michael revealed that it was supposed to have been voiced by Chris Chan.note They instead settled on Harry Partridge giving an uncannily accurate impression of Christine's voice.
God became a favorite despite his brief appearance for two main reasons. First, he's voiced by the acclaimed comedian Gilbert Gottfried who goes all out with his signature voice for the Lord. Second, viewers expressed surprise that the show averted God Is Evil and God Is Inept as is common to portray him in modern media, especially adult comedies, noting that it was more subversive and surprising to just straight up go with the God Is Good and almighty approach. When Gilbert Gottfried sadly passed away not long after his role as God in Smiling Friends, God's status as an Ensemble Dark Horse increased tenfold as fans were touched that his final voice acting role was a positive depiction of the Lord.