lonelygirl15 has had a number of these, from "Proving Science Wrong... with Lonelybeast and Danielgirl 15", in which the two main characters acted the part of each other, to "Coming For You", a threatening video posted by a Shadow.
With The Angels provides two examples, "Sunshine Film Academy", presented in the style of a commercial, and "Lifetime Achievement Award", presented in the style of a music video.
Alternate History Hub's video on the Armenian Genocide is completely different from the usual format. Not only does it not touch on anything related to alternate history what ifs, but the episode is played completely straight without the usual snark, comedic elements or background music. All to show the seriousness of genocide denial.
The reviewer Todd in the Shadows typically reviews pop music. One week, during a bout of writer's block, he instead made, um,this.
And even then, the stories are all 'protagonist in a superhero setting' except for "Tales of the MCO' in which some of the main characters sit around and watch television. And heckle.
Part two of the Extra Credits video game addiction episode consists of, instead of their normal visual pun, fast paced, analytically style show, the writer for the show giving a monologue to the audience. This is because the issue hit a little too close to home for him to write, so he decided to tell his story instead.
Speaking of JonTron, while he's no stranger to intentionally deploying the alligator, his review of Christmas with the Kranks has an amazing unintentional one where he's running around during new years getting people to give Tim Allen impressions. All is fine and well until one man seizes the mic and instead starts ranting about how churches are evil drug-selling organizations and that he's going to start his own "pure" one. Other than one brief failed attempt to get the mic back, Jon spends the entire time standing by with the best bemused and most uncomfortable expression he's ever put on film.
Jon (whispering): LET'S GET THE FUCK OUT OF HERE RIGHT NOW.
Welcome to Night Vale has a couple examples of this. The most obvious one is "A Story About You", in which the usual news style is discarded in favour of a second-person narration describing the day in the life of an 'ordinary' Night Vale citizen. "The Sandstorm, Part B", is also an example, as the majority of it is narrated by Kevin, Cecil's Desert Bluff's counterpart.
An even better example is "The September Monologues," which changes the entire episode formula. It begins differently, without the usual "Welcome to Night Vale" catchphrase, and ends without the usual "good night." The episode itself is a series of 3 monologues from various characters, each one with a brief introduction from Cecil. What is even more unusual is the lack of weather, (save 6 seconds of generic music that are immediately cut off.)
There's also The Weather, where the report stops and a song plays, typically around the climax of the episode.
Twitch Plays Pokémon Black 2 is the stream's first LP of a Pokemon ROM Hack to entirely replace a main series game, rather than being a randomized vanilla game.
"Until the Lion Learns to Speak" from Folding Ideas. Instead of analyzing stories and music, he decided to discuss Somalian culture because he's worried about Somalia's current struggles overshadowing their rich history. Especially since they were the first country and developed the first written language. At the end, he plays the Somalian song, that the title's named after, with his friend.
"Ski Patrol": A parody of an old instructional video, about ski safety.
"Dino-Sore Days": A parody of an early Disney short, starring Cro-Marmot.
"Ka-Pow!": A three-episode Spin-Off starring Flippy, Splendid, and Buddhist Monkey.
The HTF Breaks, a series of one-minute episodes.
Love Bites, a series of short Valentine's day skits.
Kringles: short Christmas episodes.
Smoochies: Animations with three options, all three of which result in the character dying.
The Annotated Series breaks up its main features (video game based movies or TV shows) with intermissions that are usually completely unrelated to the central videos but are of similarly poor quality. These are typically meant as Breather Episodes for the riffers (and by extension the audience) to use to warm up before the next feature, but sometimes the intermissions end up being so bad they usurp the main feature.
Kevin and Ursula Eat Cheap have the letters shows, often recorded in advance of con appearances as filler episodes, which generally do not include any food at all.
While The Odd One's youtube channel usually consist of his League of Legends highlights video, every once in a while, TOO upload unedited videos of games other than LoL he played during his stream.
He also uploaded full unedited LoL match of him playing the jungle, leaning more towards education rather than comedy.
Even more different is the random review of hotels that he happens to stay in for an event like PAX east, blabbering about the items in his room.
Most chapters of Sailor Nothing are straight prose, but Chapter 7 is an animation in the style of an 8-bit video game, and another is a set of four "mini-chapters" from different points of view.
Random Assault: The show runs on this. It's ostensibly a gaming podcast, but the topics are all over the place.
Unlike other Wham City projects, The Cry of Mann lacks an ARG for fans to discover and dig through in order to find extra material, with Tanking Mann and a few tweets from the cast as the only side-material on offer. As Nick Nocturne explains, the series is more in line with their live shows, which features audience participation similar to what The Cry of Mann accomplishes with the phone calls.
The Angry Video Game Nerd has two specials where he reviews film sequels with confusing names and an entire dedicated review of Teenage Mutant Ninja Turtles III. His review of the Atari 5200 also stands out as quite a bit different as he is completely unable to actually play the thing: he spends the entire episode struggling to hook it up to various video game BGMs before realizing all of his controllers are broken. He doesn't even talk about a single game.