- In a 2015 interview with The Telegraph promoting The Muppets, Kermit the Frog describes the upcoming series, "we sort of are a 'Modern Family' living in 'The Middle' in an 'Office'."
- In "The Award" (Season 5 Episode 14), Brick Heck states, after getting a new suit and faced with the possibility of not going to an event, that his whole life he had "looked like Bert and/or Ernie." This refers to Brick's horizontally- and vertically-striped shirts.
- In "Homecoming II: The Tailgate" (Season 7 Episode 7), Sean Donahue appears with longer hair and a beard, to which his mother Nancy Donahue apologetically explains to Frankie Heck, "He's just trying it out; doesn't mean anything. Jesus had a beard. And Jim Henson. And none of them were doing drugs, I can tell you that!"
- In "The Core Group" (Season 8 Episode 1), Axl Heck tells his brother Brick "That haircut makes you look like a Muppet! Not a main one. Like one that played a waiter."
- In "Ovary and Out" (Season 8 Episode 13), as Frankie and Mike Heck reminisce about their oldest son's inability to fall asleep when he was little, Frankie begins: "Axl was the worst, remember? Oh! We had to drive with him for hours. And listen to that Sesame Street cassette over and over." Mike adds: "But we had to skip that song with The Count." Frankie: "Oh yes, he was terrified of the Count! Aww!" Mike: "I always liked Oscar. The guy just liked trash, and didn't want other people messin' with it. Now why's that make him a grouch?" A short while later, Frankie starts crying: "It's just one minute, you're driving around with your kids, listening to Elmo sing "I Don't Want to Live on the Moon," and the next minute, your doctor's telling you he can't find your ovaries." After consoling his wife, Mike corrects her by adding: "I think Ernie sang "I Don't Want to Live on the Moon!" Frankie: "No. Ernie? Was it Ernie?" Mike: "I think it was." Frankie: "What'd I say?" Mike: "Elmo." Frankie laughs: "Elmo."
- Kirstie Alley played Pam Staggs in "Pam Freakin' Staggs"
- Edward Asner played Ben
- Julianne Buescher played Woman Customer in "The Cheerleader"
- Mindy Cohn played Kimberly in "The Wonderful World of Hecks"
- Brian Doyle-Murray played Mr. Ehlert (2009-2015)
- Rachel Dratch played Principal Barker
- Neil Flynn plays Mike Heck
- Whoopi Goldberg played Jane Marsh
- Patricia Heaton plays Frankie Heck
- Cheryl Hines played Dr. Sommer Samuelson
- Keegan-Michael Key played Reverend Deveaux
- Jimmy Kimmel played himself
- Jack McBrayer plays Dr. Ted Goodwin
- Doris Roberts played Ms. Risky in three episodes
- Ray Romano played Nicky Kohlbrenner
- Amy Sedaris played Abby Michaels in "The Fun House"
- Molly Shannon played Janet in two episodes
- Eden Sher plays Sue Heck
- Brooke Shields played Rita Glossner
- French Stewart played Principal Cameron
- Nicole Sullivan played Vicki in "The Walk"
- Dick van Dyke played Dutch Spence
- ↑ "Kermit opens up about Miss Piggy split ahead of new Muppets show", The Telegraph, August 5, 2015.
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