Jane is the hero of the story, but she is a supernatural entity. Whether she is a Vampire/werewolf/zombie/etc, is not important. She has a secret, and the secret must remain such because of the Masquerade... In comes Nick, Jane's best friend. They share everything, and tell each other everything. Well, almost everything.
Cue ironic statements about a show being "dead" or how it "bites". Sometimes, the show will lead up to the reveal and will harp on about the true test of friendship, with the friend now becoming a Secret Keeper. In other cases, the friend discovers it on their own and decides to continue playing dumb. It's just as common for Status Quo Is God to be in effect though, and the friend remains unknowing throughout the entire story, no matter what happens. This can be especially jarring if the nonhuman friend has obvious visual cues as to their true identity, like ever present vampire teeth, a fondness for wearing wizard gear, technicolor hair, etc.
- Bleach: Tatsuki and Ichigo were very close as children and shared everything except one thing; when Tatsuki asks if it's true Ichigo can see ghosts, Ichigo lies and says he can't. Later in life, Ichigo becomes a shinigami and Tatsuki gains the ability to see ghosts. Not only does Ichigo hide his shinigami activities from her, she hides the fact she knows about them and that she can see ghosts.
- Subverted in Kyo Kara Maoh!, in which Murata is a picture-perfect example of this trope, complete with unsuspectingly dragging Yuuri into situations where he just happens to fall into water and get dragged to the other world...until it turns out he was, in fact, in on it and facilitating all along, and knows considerably more about what's happening than Yuuri does.
- In Magical Girl Lyrical Nanoha A's, Dr. Sachie Ishida, Hayate's treating physician, is pretty much the last muggle adult kept out of the loop (that Hayate, Nanoha, etc. are magic-users). Leads to an amusing conversation in one Sound Stage, where the mages are supposed to mind their tongue around Ishida but fail repeatedly, such as when Signum is unable to bring herself to address Lindy as anything but "Admiral".
- An inversion occurs in Rosario + Vampire. Tsukune is the token human who tries to keep his humanity a secret from his friends. They're pretty blind to it for most of the first season. Eventually everyone finds out, but he manages to convince the majority of the school he isn't human. And then eventually it ceases to be an issue because Tsukune ceases to be entirely human.
- Naru/Molly plays this for Usagi in Sailor Moon...at least up to the point where she gets Demoted to Extra.
- Spider-Man keeps his identity a secret from everyone he knows; friends, colleagues, even his Aunt May. Mary Jane was the only one he let in on the secret.
- The title character is a super powered alien from another planet who disguises himself as mild mannered reporter, Clark Kent. His friend Jimmy Olson doesn't know the truth and neither do any of his co-workers. Lois Lane might or might not know Depending on the Writer. The only other muggles in on the truth are Superman's adoptive parents who may or may not be dead, and Lana Lang DOTW.
- This is played with in All-Star Superman, where Lois is the unwitting muggle friend and Jimmy is a (possibly secret) Secret Keeper.
- All four aliens in 3rd Rock from the Sun had friends and even love interests who didn't know the truth about them.
- Iris is this to Barry in the first season of The Flash, until she figures it out towards the end. Shes rather pissed to find out that her best friend, boyfriend, and father were all keeping her Locked Out of the Loop.
- Supergirl: Lena is Kara's best friend, but she has no idea that she is Supergirl until the tail end of season 4. She doesn't take it well.
- Foggy spends most of the first season of Daredevil (2015) ignorant of Matt's crimefighting exploits. When he learns about it, he is pissed.
- In Forever Knight everyone else on the police force generally, and Nick's partners Schanke and Vetter in particular, are unaware that he's a vampire. In a twist, Vetter is aware that there are vampires but she thinks that she's keeping that a secret from him.
- Both Hank and Juliette on Grimm are clueless about Wesen and Grimms, at least in season 1.
- Lucifer: The titular character's mortal friends are all this, as nobody believes his claim of being the Devil. The twist is that Lucifer never tries to hide his identity, as he never lies, after all. It's just that with him being the owner of a luxurious nightclub in Los Angeles, where practically everyone can create a persona to make it big, claiming yourself as the Devil is kind of a cliche. This gradually dissipates as time goes on, though, as they learn the truth one by one.
- Sabrina the Teenage Witch had a few like her boyfriend Harvey and best friends Jenny and Valerie.
- In Smallville, all of Clark's friends are initially unaware of his secret. All of them eventually learn it though.
- In Wizards of Waverly Place, Harper Finkle is unaware that her best friend Alex, along with Alex's brothers Justin and Max, are wizards. Once she finds out, she inevitably becomes Alex's sidekick in her magical shenanigans.
- Immortal Souls has Friendly Neighborhood Vampire John's Unwitting Muggle Love Interest, Allison. She finds his behavior and physical traits odd sometimes, but mostly worries that he's sick or is having problems rather than thinking anything major is up. Most of the games' plots involve him trying to keep her in the dark about him and the supernatural world even when she's being threatened and/or held hostage by his equally monstrous (but disguised) enemies.
- Trixie and Spud are this to Jake in American Dragon: Jake Long, before they find out early in the first season (after accidentally handing him over to one of his enemies). They become his Secret Keepers and sidekicks from that point, instead.
- In the German show School For Vampires, Sunshine is totally unaware that Oscar is a vampire. She even goes as far as dressing him up as a vampire so he can pretend he is one!