Apparently, Sam is well-aware of his actor's previous roles. When he, Dean, and the rest of a group touring Hollywood approach the studio producing Gilmore Girls, where Jared played Rory's unlucky suitor Dean, Sam instantly got uncomfortable and vamoosed. When a leshi shapeshifted into Paris Hilton to attack him and Dean (don't ask), Dean makes a jab at the real Hilton's role in House of Wax (2005), saying he never even watched it, and Sam, A.K.A. Jared, looks a little hurt.
The character Jamie in the season 4 episode "Monster Movie" was named for a sick fan.
Tracy went from a fan who writes Dean/Castiel fic and likes Misha Collins to meeting Misha and having a milkshake with him, having her friends asked where she was when she wasn't at a convention and running the charity The Random Act which Misha's minions created.
Madison also somewhat fits this; she had tea with Misha Collins and has arguably one of the best known blogs in the fandom.
An episode in Season 3 briefly featured Mercedes McNab as a girl recently turned into a vampire, harking back to her most recognizable role as the vampire Harmony on Buffy the Vampire Slayer and later Angel.
Jensen Ackles (Dean Winchester) directed the sixth season episode "Weekend at Bobby's", the seventh season episode "The Girl Next Door", the eighth season episode "Heartache" and the tenth season episode "Soul Survivor".
Misha Collins (Castiel) directed the ninth season episode "Mother's Little Helper".
In the pilot, Jared Padalecki was asked to take Jensen Ackles by surprise when pulling him into the motel room.
During Castiel and Dean's first meeting, Misha Collins has stated he got much closer into Jensen's personal space and stared at him much more blatantly than in rehearsals, just to enforce how Castiel is unused to human interaction. Jensen's squirming and uncomfortable reaction is real.
Later on in Season 4 when Azazel is possessing Samuel Campbell, Mitch Pileggi apparently decided to sniff Jensen's neck just to get the squicked-out reaction seen on camera.
Due to the parallel between the two sets of brothers, Television Without Pity have dubbed Sam and Dean collectively "The Hardy Boys". This was actually used in "Abandon All Hope..." and "A Very Supernatural Christmas".
Sam and Dean also have their own individual nicknames on Television Without Pity: Dean is known as "El Deano" or "Dashing El Deano", "Ducky Lips" (A.K.A Dean's pouty mouth), and "Li'l Stumpy" (referring to his bowlegs and his lack of height in comparison to Sam). Sam has been dubbed "Sasquatch", "Moose", "Gigantor", and "Sam the Ginormotron", all in reference to his height; "Puppy", and "Darling Sammy". "RoboSam" was used to refer to Sam without a soul in Season 6.
John: Daddy Shut Up/Shut Up Daddy—a nickname applied to John on Television Without Pity, who has taken a lot of heat across the forums and in the recaps for his actions (or non-actions) and the consequences of those on the show. Also "Papa Winchester".
The Impala is known as "The Metallicar" in fan circles, in part for the type of music that is often played on its stereo. Also from Television Without Pity, but it's even been picked up by TV Guide. It's also the Trope Namer for Metallicar Syndrome. When Sam merged with the Impala in "Changing Channels", fans dubbed it the "Sampala".
The show's creator, Eric Kripke, is nicknamed "the Kripkeeper".
In the early days, Meg was called "Demon!Meg" to tell her apart from her host (who was called "Human!Meg" or "Real!Meg" for the same reason). Most of the fandom has stopped doing this because demon!Meg rose into much greater prominence than her first host and stuck around way longer, to the point that nowadays it's generally expected that when you're talking about Meg, you're talking about the demon who possessed her instead of the human herself. As with Ruby, you may also find people discussing the differences between "Blonde Meg", "Meg 1.0", or "Nikki's Meg" for the first-season version of the character, "Evil!Sam" or "Meg 2.0" for the second-season version of the character, and "Brunette Meg" or "Rachel's Meg" for the last incarnation.
YED is a common fan abbreviation for the Yellow-Eyed Demon.
In the style of Azazel's Fan Nickname, there's CRD (crossroads demon) and RED (Red-Eyed Demon) for crossroad demons in general. The specific crossroads demon who appears in "Crossroad Blues", "All Hell Breaks Loose, Part Two", and "Bedtime Stories" is also sometimes called "Dean's crossroads demon" (even on This Very Wiki), since there are multiple crossroads demons and she mainly appears to Dean.
Fans use nicknames to differentiate between the actresses portraying Ruby. "Blonde Ruby", "Old Ruby", and "Ruby 1.0" refer to Ruby as portrayed by her original actress, Katie Cassidy. "Brunette Ruby" (or "Dark Ruby"), "New Ruby", and "Ruby 2.0" refer to Ruby as played by Katie's replacement, Genevieve Padalecki. To a lesser extent, Anna Williams' Ruby is called "Secretary Ruby" or "Ruby 1.5" and Michelle Hewitt-Williams' Ruby is "Maid Ruby" or "Ruby 3.0".
Castiel: Cas, Clairestiel (when possessing Jimmy Novak's daughter Claire's body), Thingstiel (Castiel's celestial form), Godstiel (after Castiel declared himself God).
Alastair: Fake Brando. A Television Without Pity-coined nickname for Hell's best torturer in Season 4, who, no matter what host he is in, always sounds like he's doing an incredibly horrible Marlon Brando impression.
Lucifer: Lucy; Samifer—Lucifer in Sam's body; Markifer—Lucifer in Nick's body (named for actor Mark Pellegrino); Hallucifer—Sam's hallucinations of Lucifer.
Deanmon or demon!Dean for Dean as of the season 9 finale.
Hardison must be running one hell of a con in "All Hell Breaks Loose, Part One" and "All Hell Breaks Loose, Part Two".
Mr. Gibbs is Frank Devereaux, the conspiracy theorist who destroys Sam's laptop.
Meg Masters (Nicki Aycox) is Max's sister Syl from Dark Angel. Max's brother Ben was played by Jensen Ackles, so Dean and Meg's actors have played brother and sister, albeit not appearing in the same episode.
Finn gets eaten by the wendigo in the second episode of season 1.
Also from Glee, TV station manager Mr. McClung is the angel Zachariah.
This show is positively squee-worthy for Stargate SG-1 fans: Daniel Jackson, Jonas Quinn, Carolyn Lam, Janet Fraiser and General Hammond have all popped up, and Ellen Harvelle was the Tok'ra from the Season 2 finale.
Romance on the Set: Thanks to Season 4 of Supernatural giving the couple the opportunity to meet, Genevieve Cortese (who plays Ruby) is now Genevieve Padalecki. Which makes the sex scene with her husband (who plays Sam) in "I Know What You Did Last Summer" weirder to watch.
Jensen got to play two Deans in "Dream a Little Dream of Me" and "The End". The former was a demonic version of Dean, the latter Dean's future self in a Crapsack World.
Jared Padalecki plays three different versions of Sam in "The Man Who Knew Too Much", and while only two of them are ever onscreen at the same time, it still veers into this trope a couple of times.
In "Swan Song", Padalecki plays both Lucifer while he's possessing Sam's body, and Sam himself. The two hold a conversation through a mirror.
Trolling Creator: Eric Kripke released spoilers that Sam would have a new waitress Love Interest named Kristy in Season 4. He was kinda telling the truth (Sam had sex with a "Kristy" in the fourth season premiere, but she's actually the demon Ruby lying about her identity to cover up their involvement from Dean and Bobby), but he admitted that he was just saying it to rile up thefans. It worked.
Jason Voorhees (and not a Captain Ersatz) was originally going to appear in "Dream a Little Dream of Me". So was John Winchester, an apparition of whom would confront Dean during the climax. Unfortunately, Jeffrey Dean Morgan wasn't available at the time, so they replaced him with Jensen Ackles and did the "I'm my own worst nightmare" thing instead.
Kripke's original idea for the show was more like equal parts X-Files and Scooby-Doo. It was originally an anthology series about two tabloid reporters who travel around in a van fighting demons. Then, after the show got reworked into what we now know and love, it was originally "Sal and Dean Harrison" travelling around in a '65 Mustang. The names were changed for legal reasons (as was their father's, which was originally Jack) and the car was changed because a friend suggested an Impala is a rougher, more aggressive-looking car (and because it's easy to fit a body in the trunk).
Jess, several times! First off, she lived in one of Eric Kripke's earlier drafts for the pilot, and the network wanted her to stay, but Eric thought that one of the main characters having a long-term girlfriend wouldn't work for a roadshow about two brothers. Apparently, the idea that she could come with them and become a hunter herself didn't occur to him. Then the network suggested that he have her turn out to be a demon manipulating him, but he didn't use that, either, until he introduced her real killer in "The Devil You Know", a college friend of Sam and Jessica's who became possessed by one of Azazel's minions and manipulated Sam into going back to hunting by tricking him into falling for Jess and then killing her in front of him. Finally, Sera Gamble had Jessica planned to be one of Sam's Witnesses in "Are You There, God? It's Me, Dean Winchester", but Adrianne Palicki was unavailable and they replaced her with Ronald Reznick from "Nightshifter".
Misha Collins' Castiel role was only supposed to last for six episodes in season 4, reportedly leaving Anna to fill in as the Winchesters' angelic adviser. But positive fan reaction not only brought him more screentime and A Day in the Limelight that season, but the character was promoted to the main cast the following season and has remained a major character ever since.
Lenore from "Bloodlust" was supposed to have Meg's role in "Caged Heat"—teaming up with the Winchesters to find and kill Crowley, which makes sense, considering he was hunting her kind down for Purgatory—but Amber Benson couldn't appear, so her part had to be rewritten and Meg and her merry gang of Lucifer loyalists appeared instead.
The biggest of them all: had season 3 gotten a full 22 episodes, Sam would have discovered a way to save Dean from his deal, and the entire angel mythology never would have come into the show.