A team of five soldiers—Duke, Ripcord, Tunnel Rat, Roadblock and Scarlett (with Snake Eyes helping from the shadows)—are sent to investigate Cobra Pharmaceuticals. They discover Cobra's new top secret weapon, Bio-Vipers, but are discovered and are forced to blow the facility to save themselves; though seemingly at the cost of Ripcord's life.

After surviving the Cobra Pharmaceuticals explosion, the team are framed for it and become known as the "Renegades" by the media. They then go after a surviving Bio-Viper that's heading to Springfield. While Baroness and Doctor Mindbender oversee the "quarantine," General Abernathy sends Flint to get Lady Jaye to help him bring in Duke's team.

Posing as a preacher that helps veterans, Scrap-Iron kidnaps Tunnel Rat and uses him to test a weaponized "exo-armor" suit for James McCullen and M.A.R.S. Industries. He meets Ralph Pulaski (a.k.a. Steeler) in another suit and they must battle each other to survive. Roadblock then attempts a rescue by allowing himself to be captured, but he is forced into an exo-suit as well. Now the rest of the Joes have to save him too.

The Joes make a pit stop in a small town in Kansas and quickly find themselves tangling with the Dreadnoks, their leader Zartan, and a cowardly local sheriff. Now they must race against time to help the locals free themselves from the biker gang's reign of terror, give the sheriff his courage back, put the whole gang behind bars, and get out of dodge before Flint arrives to arrest them.

The Baroness contacts mercenary, Major Bludd, to track down and assassinate a target—-a former Cobra employee turned internet blogger-—who they believed stole one of their data scanners, only to learn he's under the Joes' protection.

The Joes take refuge at Snake Eyes' dojo where they train with him and meet his first apprentice, Jinx. They also learn about his connection to Jinx's cousin Storm Shadow and their connected past to the Arashikage ninja clan.

Duke is wrongfully imprisoned when he gets caught up in a chop shop while looking for a replacement part for their vehicle. The rest of G.I. Joe must break him out of prison by having Roadblock get arrested. They soon discover that the prison warden is making prisoners fight each other for his amusement. Now the Joes must get Duke and Roadblock out and expose the illegal activities in the prison.

Adam DeCobray, head of Cobra Industries, hires James McCullen of M.A.R.S. Industries to combine Dr. Mindbender's Bio-Vipers with the failed MARS exo-armor suits. Meanwhile, the Joes infiltrate the Cobra lab after receiving information of DeCobray's plans, from a masked whistleblower. During the attempt, Mindbender reveals a deadly secret, leading DeCobray to reveal himself as Cobra Commander. James McCullen becomes an iron-masked "Destro" (estranged/alienated one) as a symbol of his failure, betrayal and servitude to Cobra.

When the town of Green Ridge issues a court order to Cobra Industries to halt the construction of their dam, Baroness and Doctor Mindbender send Firefly to burn this former resort town to the ground, leaving it up to G.I. Joe and a local firefighter to stop him.

Duke heads home to Missouri to protect his family from Cobra, while the Joes infiltrate Cobra Industrie's Christmas party in Washington D.C. Duke's (adolescent) past with Flint during a high school state football championship is revealed.

With the Joes in Flint's military custody en route to DC aboard a military train, the Baroness tries to regain a hard drive holding Cobra secrets. Now dubbed the "Springfield Four" the Joes' identities are compromised in the process. Storm Shadow via the Baroness, forms an alliance with Cobra.

Running a cult commune and fleecing the initiatives of their money, psychic twins Tomax and Xamot hypnotize most of the Joes after they find Sister Leia wandering in the desert. Meanwhile, Doctor Mindbender is seeking a psychic in order to learn the secrets to mind control for his Bio-Vipers.

Introducing Characters: Tomax and Xamot, Crimson Guard

Flint and Lady Jaye offer Zartan a reduced sentence for his help. Meanwhile, the Baroness transports a camouflage suit—-technology that can duplicate anyone's appearance—-to Cobra Commander, but Zartan accidentally ruins everyone's plans. The Joes and the Falcons, must capture Zartan and retrieve the camo suit.

Dr. Mindbender creates prototype "Shadow-Vipers", synthetic doppelgangers of Storm Shadow, to track down the Joes, who are now in Canada hiding out with Snow Job, Tunnel Rat's old arctic trooper buddy. But Snow Job doesn't give the team the warm welcome they expect. There, Snake Eyes rescues a timber wolf caught in a hunter's trap.

A sea captain, Hector Delgado, helps the Joes transport a canister commandeered from Cobra's arctic lab to General Abernathy in Washington D.C., evidence that would expose Cobra Industries' illegal activities and clear their names. On board his ship, Courtney, a prototype Techno-Viper is freed from its canister.

Introducing Characters: Shipwreck, Cover Girl (in a poster as Courtney Kreiger), USS Flagg, Techno-Viper

Tracing the prototype Techno-Viper's signal, following its defeat, the Joes end up in Scotland, and become trapped inside Destro’s castle during a recon mission. They discover the Bio-Dag, a missile that dispenses Bio-Vipers en-masse.

The Joes infiltrate a corporate tele-communications summit at the Cisarovna chateau in Russia. They uncover a mind-control scheme involving Cobra Industries' new "Black Adder" cellphone. However, the Joes discover a local with an axe to grind against the Baroness and her family, and he's willing to sacrifice everyone's life for revenge.

Introducing Characters: Red Star (of the Oktober Guard)

The Joes uncover the deadly Anaconda Strain (a mammalian virus engineered from reptile DNA) while searching for a missing biochemist, Dr. Kurt Schnurr, in Mexico. They also learn of Cobra's plan to profit from the sale of its antidote once they've released it onto the unsuspecting populace.

The Joes raid a Cobra medical facility to search for "Patient X" (the originator of the Anaconda Strain) and any other information that would help them prevent an outbreak. They soon discover that Patient X is actually an amnesiac Rip Cord and help to regain his memory. Unbeknownst to them, he has been turned into a Bio-Viper/human hybrid by Doctor Mindbender and Cobra can track his movements.

Doctor Mindbender's attempt to create another human/Bio-Viper hybrid appears to be a failure at first until it ends up reassembling in the New York City sewer system. When Duke, Roadblock, and Ripcord go along with Tunnel Rat to his hometown of Brooklyn to find a missing child named Reggie, they encounter the Sewer Viper being pursued by Doctor Mindbender. When the mad scientist tries to reclaim Ripcord for Cobra, the Sewer Viper removes the control chip in his head, giving the Joe full control of his Bio-Viper form.

Flint hires Corporal Hershel Dalton (aka: Heavy Duty) to apprehend his estranged cousin Roadblock while he (and the team) is in his hometown of Biloxi, Mississippi for their grandfather's funeral. Major Bludd chases the cousins through the bijou, but loses them ...and an arm to a gator.

Scarlett and the Joes go to her hometown of Atlanta, Georgia where she visits her vacant, family home. She learns from footage recovered by Snake Eyes that her father, professor Patrick O'Hara, invented the Molecular Assembler Scrambler Sender (a.k.a. the MASS Device) for Cobra Industries. Meanwhile, the Baroness commands the Bio-Vipers to attack the Joes when Cobra realizes the stone in Scarlett's locket is an integral part of the MASS device.

Introducing Characters: Professor Patrick O'Hara (Scarlett's father)

As Scarlett's locket is in Baroness and Doctor Mindbender's possession, the Joes decide to take the fight to Cobra Industries by infiltrating their stronghold and stop them from finishing the MASS device. After a climactic fight, the Joes arrive in Washington D.C. in Destro's High Speed Sentry (a.k.a. HISS tank) and are surrounded by General Abernathy and the Falcons. Scarlett shows them the proof they need to clear their names. In the end, Cobra Industries' secrets are revealed and Cobra Commander declares war on the Joes.

Trivia #1: The original broadcast included a trailer segment showcasing the 1980s Sunbow cartoon version of Duke stating the Renegades reality was "just a dream", specifically separating the two interpretations. The other counterparts of the Renegades crew refute the Renegades reality, laughing at the description Real American Duke tells them.

Trivia #2: The H.I.S.S. tank along with Destro's signature outfit are featured, and the Cobra Night Raven can be seen on a Cobra computer screen