- Guardians of the Galaxy
- Spider-Man / Peter Parker
- S.H.I.E.L.D. Academy students
- Inferno / Dante Pertuz (first appearance)
- Luna Snow (first appearance)
- Mister Fantastic / Reed Richards
- Invisible Woman / Susan Storm
- Max Modell
- Flash Thompson
- Hector "Hercules" Quill
- Kree Empire
- Man-Wolf / John Jameson (first appearance)
- J. Jonah Jameson (mentioned only)
- Midtown High School
- Raymond Warren (mentioned only)
- Harry Osborn
In a unknown asteroid, John Jameson, the son of J. Jonah Jameson, is seeking an artifact to help him earn heroic recognition, enough to help clear his father's name out of his actions. Entering a forbidden chamber, he obtains a lunar gemstone and takes it to Earth. Back on Earth, the gemstone spreads to life and, before Jameson is greeted by fellow astronauts, mutates Jameson into a feral wolf monster, and begins wreaking havoc.
Meanwhile, Nathan Quill, Zoe Gillan and Peter Parker are on their studies at Baxter Institute as Nathan's older brother Hector "Hercules" tries to bust Flash Thompson out of community detention, but he gets distracted and fails when he sees Luna Snow (a Ice Elf/Inhuman hybrid and trainee in S.H.I.E.L.D. Academy) walking by with her boyfriend and fellow trainee Dante Pertuz / Inferno for a visit in Baxter Institute. Later on, followed by Reed Richards / Mister Fantastic and Susan Storm / Invisible Woman, Nathan, Zoe and Peter suit up as Star-Lord, Gamora and Spider-Man when the New York Penitentiary is attacked by Jameson (addressed by local witnesses as "Man-Wolf"), who is trying to break his father out of prison. The five defeat him and force him to retreat, but not before Star-Lord and Mister Fantastic expose Man-Wolf's identity with some remnants of Jameson's NASA uniform in it. Meanwhile, Drax the Destroyer, Rocket Raccoon / Sebastian Allan, Groot, Nebula, and Yondu Udonta battle a Kree squad sent by Yon-Rogg to attack NASA in search for Man-Wolf. They defeat the invaders with help from Inferno and Luna, forcing Yon-Rogg to retreat while Rocket hijacks one of the Kree troopers' communicators to overhear of Yon-Rogg's next schemes. As he tries to (but fails) to revert his Man-Wolf form, Jameson overhears news about his identity having been exposed to the public by eyewitnesses from NASA, and is shocked to hear has he has ran out of resources to release his father from prison. Worse, his fiancee has decided to end his relationship to avoid involvement. Later on, he overhears news about the day his father went to prison, Jameson becomes convinced that Thompson (who had been the main cause of his father's downfall) is responsible for his condition, and plans to kill him in revenge.
Later at night, while Mister Fantastic and Invisible Woman explore the asteroid which Jameson went into, Star-Lord, Gamora, and Spider-Man are with Inferno and Luna investigating the wreckage on the NASA compound, discovering the chattered, but still unstable lunar crystal responsible for Jameson's Man-Wolf condition, while Rocket and Nebula keep Yon-Rogg's crew in check, during which they overhear of his plan to capture Man-Wolf and turn him into the Kree Empire's beast machine Super-Soldier. Harry Osborn comes by to collect the lunar crystal shards for experimentation, despite Luna's warnings about how dangerous they might still be. Meanwhile, Hector succeeds in breaking Thompson out of the community detention while plotting to sabotage Nathan and other Baxter Institute students, unaware they were being observed by Star-Lord and Gamora through Drax and Cougar (who were at the time keeping their eyes on Hector). Just then, Man-Wolf resurfaces and ambushes Thompson, chasing him and Hector around streets as Drax and Cougar change to their beast forms and hold him off until Star-Lord, Gamora, Spider-Man, Inferno and Luna arrive to fight him. In a Oscorp facility, scientists are analyzing the shards until they are ambushed by Yon-Rogg and his crew, who are soon taken to a fight by Rocket, Nebula, Yondu and Groot. Man-Wolf soon lets out a beastly howl which triggers the lunar shards in Oscorp, turning both Oscorp scientists and members of Yon-Rogg's crew into feral werewolves.
As Rocket and Nebula create a force field around the facility to prevent the werewolves from escaping, Yon-Rogg rushes to capture Man-Wolf alone, but is beaten and forced to retreat empty-handed. Mister Fantastic and Invisible Woman arrive to inform the Guardians that they can revert the effects of the lunar crystal by destroying its "heart ruby", which is in Man-Wolf's possession. As the others fight the werewolves off, Star-Lord, Spider-Man, Gamora and Luna and Inferno subdue Man-Wolf and strip him off the heart ruby and destroying, reverting the Kree soldiers and Oscorp scientists back to normal, although Jameson (due to longer exposure to the lunar crystal) remains permanently transformed into Man-Wolf. As Man-Wolf is incarcerated in the Vault, Hector and Thompson try to invade Baxter Institute for their planned sabotaging scheme until police officers (having been informed by Peter and Nathan of their mischief) apprehends them and sentences them for permanent community detention, as Hector is reportedly expelled from Midtown High. Watching the news, Peter finds himself concerned that his former classmates from Midtowh High will be furious at him for this, but Nathan and Zoe assure him that in the end, only the jocks will be to blame for their failure... as will their principal Raymond Warren. Next night, Nathan and Zoe enjoy a double date with Inferno and Luna, as they had agreed to.
- Scott Menville as Star-Lord / Nathan Quill
- Laura Bailey as Gamora / Zoe Gillan
- Haley Joel Osment as Spider-Man / Peter Parker
- Scott Porter as Inferno / Dante Pertuz
- Ashly Burch as Luna Snow
- Troy Baker as Rocket Raccoon / Sebastian Allan
- Travis Willingham as Groot
- Erica Lindbeck as Nebula
- William Salyers as Yondu Udonta
- Alan Tudyk as Mister Fantastic / Reed Richards
- Catherine Taber as Invisible Woman / Susan Storm
- Fred Tatasciore as Yon-Rogg
- James Arnold Taylor as Man-Wolf / John Jameson Hector "Hercules" Quill
- Sam Riegel as Harry Osborn
- Will Friedle as Flash Thompson
- The title of the episode is based on the title of the 1998 song "Who Let the Dogs Out?" by Baha Men.
- "(I Just) Died in Your Arms" by Cutting Crew