Robert’s son (Alan’s half-brother) Tony was also on an episode.
Emilio Estafan appeared in an recent episode of 2 1/2 Men as Charlie’s best friend.
Brad Pitt was on an episode of Friends against then-wife Jennifer Aniston, playing the head of the “I Hate Rachel Green” squad. It was revealed that he started the rumor that Rachel was born with a “tiny weenie.”
Justine Bateman appeared in Arrested Development as a hooker unrelated to Jason Bateman’s character.
Will Arnett’s wife also appeared in the show, playing his character’s wife. Not sure how that fits in the OP.
If your surname was Van Dyke, then you’d be in Diagnosis Murder at some point.
Shane Van Dyke became a semi-regular cast member as Alex Smith, alongside his dad (Barry) and grandfather (Dick). Looking on IMDb, it seems he appeared in three other episodes as three different characters before that. Also popping up in little roles were the rest of his siblings (Carey, as six characters in six episodes; Wes, as three characters in three episodes; Taryn, as two characters in three episodes).
Dick’s brother and daughter also appeared but don’t count because they played his character’s brother and daughter.
The series should’ve been called Diagnosis Nepotism.
I just happened to see an episode of “Roseanne” in which she & Jackie get pulled over by a pair of cops. Trying to sweet talk their way out of a ticket, Roseanne starts telling one of the cops how much she respects the work they do, how difficult & dangerous it is, how brave he must be to be an officer. The cop cracks back (paraphrasing) “Hey, this is nothing. At the end of the day, I have to go home to my crazy wife.” The officer was being played by Rosie’s husband-of-the-moment. (Not Tom Arnold, the guy she dumped him for.)
Going way back, there’s a classic in-joke on an episode of “That Girl!” Marlo Thomas is visiting a Catholic rectory and pauses at a drinking fountain. As she’s turning around, she accidentally bumps into a priest. They have this exchange…
Marlo: “Oh, excuse me Father.”
Priest: “That’s quite all right, my child.”
Of course, the priest was being played by Danny Thomas - Marlo’s RL father.
Not only that, Kal, but over the last few years Dick and Barry Van Dyke have starred in three TV movies (on the Hallmark Channel) playing a criminology professor and an unrelated private investigator. Shane was in one of them, and Shane and Carey were in the most recent. I think Shane’s character was Barry’s nephew in one movie, but not the other.
The Sheens do this a lot:
Charlie & Emilio unrelated cowboys who hated each other in “Young Guns”.
Charlie & Emilio unrelated garbagemen in “Men at Work”.
Charlie played a private and Martin a going-round-the-bend Sergeant in “Cadence”.
Martin had an “Apocalypse Now” cameo in Charlie’s “Hot Shots Part Deux”.
Charlie had a cameo in Emilio’s “Loaded Weapon 1”.
Jeanne Cagney appeared in A Lion is in the Streets as a character unrelated to her brother James’s. (She also twice played Cagney’s sister in other movies.)
In most Marx Brothers films, Chico’s character was not Groucho’s brother. Harpo was usually not Groucho’s brother, either, though he and Chico were sometimes brothers. Zeppo was often Groucho’s secretary, not his brother (though he did play Groucho’s son in Horsefeathers).
John Barrymore played The Baron in Grand Hotel, opposite his brother Lionel, who played Otto Kringelein.
Moe, Curley, & Shemp Howard (aka Moses, Jerome, & Samuel Horwitz) weren’t related in many/most of the 8 billion Three Stooges shorts.
I think the prize has to go to Jack Garner, brother of James Garner. According to IMDb, he appeared in 26 episodes of The Rockford Files, playing at least 19 different parts.
You could cite Ryan and Tatum O’neill in Paper Moon, but the audience knows all along that their characters are really father and daughter, even if “Mose” never admits it.
Ben Stiller and his father Jerry appeared in “Zoolander” together, but not as father and son (Jon Voight played Ben’s father in that one).
Tom Hanks and his wife Rita Wilson both appear in “Sleepless in Seattle,” but she plays Victor Garber’s wife, not Tom’s.
Nia Vardalos’ husband, Ian Gomez, appears with her in “My Big Fat Greek Wedding,” but her character marries John Corbett, not Ian.
Similarly, Ken Olin and Patricia Wettig, married in real life, co-starred in “Thirtysomething,” but their characters were married to other people.
Although it wasn’t specified that Moe & Curly were playing brothers, it wasn’t clear that they weren’t, and their real surname was used at least once. (“Calling Dr. Howard, Dr. Fine, Dr. Howard!”)
Also Charlie has a very brief cameo as Emilio’s boss who fires him near the begining of “Wisdom”.
Both Martin Scorcese’s parents appeared in Goodfellas. His mother played Joe Pesci’s mother and his father played a gangster in the prison scenes.
Additionally, Christine Taylor and Ben Stiller were both in Dodgeball, and I think a few other movies. (They did play themselves – or versions of themselves – on Curb Your Enthusiasm.)
TV series It’s Always Sunny in Philadelphia has two sets of married couples who play unrelated singles.
Charlie Day and Mary Elizabeth Ellis play Charlie Kelly and the coffee house waitress
Creator Rob McElhenney and Kaitlin Olson play Mac and Sweet Dee Reynolds
A reoccurring theme in the series as that Charlie pursues the waitress who finds him disgusting.
Charley Chase and his brother James Parrot appeared in two movies together, and did not play relatives.
Walter Huston and John Huston were both in The Treasure of Sierra Madre. John played an American tourist and never appeared with Walter.
I seem to recall that Eddie Van Halen appeared in an episode of Valerie Bertinelli’s sitcom “Cafe Americain” as an itinerant guitar player who bothers her (this was while they were married).