Flip-Flop of God: When first announced, this cartoon was said to take place in the same universe as Ultimate Spider-Man. However, later information stated it would be a sequel to The Avengers: Earth's Mightiest Heroes!, which took place in a different universe. However, while it would later be clear it's set in the same universe as USM, as noted below, a true sequel to EMH was in the works before Marvel pulled the plug on it for a show closer to The Avengers (2012), so this could be the result of that happening.
I Knew It!: Many fans weren't the least bit surprised that Truman Marsh turned out to be a bad guy, but didn't think he'd be Ultron. Needless to say, there are plenty of Jerkasses in this series, but Marsh was too much of one to be legit. Behaviors such as lack of regard for the lives the Avengers saved, or Red Hulk's destructiveness definitely raised a red flag.
Irony as She Is Cast: "Prison Break" has Crimson Widow, a villain, fighting Wasp, a hero. They're respectively voiced by Julie Nathanson and Kari Wahlgren, who are best friends in real life.
So far, every post-Season 2 appearance of Tony Stark/Iron Man intended (or implied) to take place in the Ultimate Spider-Man universe has him voiced by Mick Wingert instead of Adrian Pasdar. This includes Lego Marvel Super Heroes: Avengers Reassembled and Marvel Super Hero Adventures: Frost Fight!. Mr. Wingert took over the role full-time beginning with Secret Wars, though we get a taste of it in Guardians of the Galaxy (2015).
In "Planet Doom" and Hulk and the Agents of S.M.A.S.H., Fred Tatasciore voiced Bruce Banner in addition to the Hulk. In "Adapting to Change", Jesse Burch voiced Bruce. Starting in season 4, Bruce Banner is voiced by Kevin Shinick, the show runner of Marvel's Spider-Man .
Heimdall was previously voiced by James C. Mathis III in the first two seasons, and by NBA star Chris Bosh in the Hulk and the Agents of S.M.A.S.H. episode "For Asgard." In "The Most Dangerous Hunt," he's instead voiced by Kevin Michael Richardson, who reprises his role from Guardians of the Galaxy.
In Ultimate Spider-Man, Klaw was voiced by Matt Lanter. Here, he's voiced by David Shaughnessy. In Season 5, he'll be voiced by his Lego Marvel Super Heroes - Black Panther: Trouble in Wakanda voice actor, Trevor Devall. Likewise, Shuri's voice actress from the LEGO special, Daisy Lightfoot, will replace Kimberly Brooks as Shuri.
Ant-Man was voiced by Grant George for the first three seasons, before being replaced by Josh Keaton beginning in Secret Wars.
When he appeared in season 2, Howard Stark was voiced by Stephen Collins and in season 4 by Charlie Schlatter. This likely has to do with TMZ leaking recordings of Collins confessing to his ex-wife to child molestation.
Sticking with season 5, Crystal is voiced by Stephanie Sheh instead of Mary Faber (HATAOS) and Vanessa Marshall (GOTG).
Out of Order: Several epsidoes of Season 4 only make sense if they're assumed to take place before the Season 3 finale. Specifically:
The Halloween Episode, which only features the original Avengers (including Iron Man, who still cannot escape the dimension he is in) and none of the new recruits like Black Panther or Ms. Marvel, and yet aired after the originals had been scattered across time and replaced, but before any of them had been rescued.
"New Year's Eve," features Avengers Tower despite it having been destroyed, and Iron Man, who was still isolated in a Prison Dimension when the episode aired. However, this placement was done intentionally as the writers wanted to create a plausible story featuring Peggy Carter and Howard Stark teaming up with Iron Man and Captain America; it is technically a Whole Episode Flashback from the perspective of a time travelling Howard Stark and Peggy Carter, giving it more fluidity.
Season 3 features Ultron as the main antagonist, followed by an adaptation of Civil War, despite the "Avengers Disassembled" arc from Season 2 having already done the same basic premise. Justified slightly in that Season 3 is done by a new creative team.
Season 3 also has a mini-arc where the Hulk is forced off the team by government interference, only to be replaced with the Red Hulk. Avengers: Earth's Mightiest Heroes had a similar episode in its second season.
Marvel Super Hero Adventures: Frost Fight!, a 2015 Christmas Movie Special that primarily features the Avengers, sees Antony Del Rio reprise his role as Reptil while Grey DeLisle Griffin is once again Captain Marvel.
Keston John, Daisy Lightfoot, and Trevor Devall will reprise their respective Lego Marvel Super Heroes - Black Panther: Trouble in Wakanda role as Killmonger, Shuri, and Klaue.
In Season 4, Hayley Atwell reprises her role as Peggy Carter from the movies and Agent Carter. Wynn Everett also reprises her role as Whitney Frost from the aforementioned Agent Carter for Season 4's Halloween Episode.
Screwed by the Network: The show was lucky to have reruns as it went on. Once 2018 came around, it's only time slot is on Sunday mornings, and even then, it's mostly for new episodes. Season 5 continues this, with new episodes still premiering on Sunday, but at 9:00pm
Voices in One Room: As per usual with most projects that have Collette Sunderman as the voice director, the voice actors record together in order to really get that character chemistry going.
Early promotional art and footage had Hawkeye wearing his red outfit from The Ultimates and the movie. In the final show, his outfit is purple rather than red, making it resemble his current comic book look◊.
Before a creative team shakeup behind the scenes, the original plan was for Season 3 to directly follow the ending of Season 2. When Eugene Son and Dani Wolff took over as story editors in Season 3, the initial premise was abandoned.
Moon Knight was planned to appear in Season 3 (hence the tease in the Season 2 finale), but because of the aforementioned behind-the-scenes shakeup, his appearance was pushed back to Season 4.
A spinoff based on the Carol Danvers Captain Marvel was proposed, but ultimately never got off the ground.
When Kamala Khan appears in season 3, it will be her first appearance in animation.