The series is notably the first work within this continuity to not focus on the Autobots and the Decepticons' war on their home planet of Cybertron (though glimpses of it are shown in various flashbacks), and instead takes place primarily on Earth during modern times.

The team operates from a former American military missile silo near the fictional town of Jasper, Nevada, and tries to conceal their existence from humanity while continuing their fight against the Decepticons.

Following Megatron's return, he uses Cliffjumper's corpse as a test subject for Dark Energon, which he intends to use to create an undead army from Cybertron's fallen warriors.

However, some episodes feature other antagonists, such as Skyquake, an ancient Decepticon warrior who is awakened by Starscream to eliminate the Autobots, only to be killed by them; Makeshift, a shape-shifting Decepticon who impersonates Team Prime's ally Wheeljack to find their base (though he is killed before he can actually reveal its location to Starscream); M.E.C.H., a human organization led by the villainous Silas who seek Cybertronian technology for their ultimate goal of establishing a new world order; and Airachnid, Arcee's arch-enemy who killed her former partner Tailgate and pursues her own vendetta against the Autobots, but eventually joins the Decepticons' ranks to become commander.

The Autobots and Megatron join forces to prevent the rise of Unicron, who is ultimately defeated after Optimus uses the Matrix of Leadership to knock him back into hibernation, at the expense of his memories.

The third season, subtitled Beast Hunters, opens with Team Prime divided and on the run from the Decepticons, while the severely damaged but still alive Optimus is being looked after by Smokescreen.

New characters are again introduced, namely Ultra Magnus, Optimus's second-in-command and the leader of Bulkhead and Wheeljack's old team, and the coldly logical Decepticon scientist Shockwave, who plans to create an army of Predacons to serve Megatron, starting with Predaking.

Despite this, the Decepticons remain an active threat, and Shockwave continues work on his Predacon army, until Megatron orders him to terminate it, pinning its destruction on the Autobots, after Predaking shows signs of intelligence and the ability to transform into a robot.

He infects most of the Nemesis' crew before freeing Airachnid (who was retrieved by the Decepticons following the Autobot base's destruction), who puts him out of his misery and claims back leadership of the Insecticons.

During the battle, Soundwave is trapped in the Shadowzone (a parallel dimension created by the interaction of multiple Ground Bridges), and Bumblebee is mortally wounded by Megatron.

Meanwhile, Unicron reanimates and possesses Megatron's body, and with the power of Dark Energon at his fingertips, he seeks to kill Cybertron's core, which is actually his brother Primus, and eliminate all those who oppose him.

[10] During the same month, it was also announced that following the series finale, a TV movie called Transformers Prime Beast Hunters: Predacons Rising would air and would end the story.

Discussing ideas about the show's themes and inspirations, Orci said that while the live-action film series was "about a boy and his cars", the dynamic between the kids and robots in Prime was to be more like that of The Iron Giant.

[13] In a similar statement, Josh Keaton (Jack Darby) revealed in a November 29, 2010, interview with The Trades that while the show does include human main characters, and their relationships with the Autobots are important, they are in the foreground.

[14] According to Jeff Kline, from the beginning they had created a story bible of at least "three years' worth of [storylines]" and that "the universal need to find or forge a family and a home" was one of the major themes when developing the series.

[16] Regarding Arcee's inclusion in the main cast, Orci said that he regretted killing her off in Transformers: Revenge of the Fallen and that Prime gave them "a chance to do what [they]’ve always wanted to do with her".

"[19] In a different interview, Peter Cullen (Optimus Prime) said that "the writing is consistent with that of the original series, though in this new version [... my character] has a lot more communication with earthlings, and so he tries to be a little more Earthlike".

Regarding Optimus' memory loss and joining the Decepticons, Duane Capizzi said that they wanted to satisfy fans' expectations "but take it in unexpected directions.

[27] Kline would later reveal that Hasbro Studios had placed high importance in getting Cullen and Frank Welker to reprise their roles as Optimus Prime and Megatron respectively.

[16] Steven Blum (Starscream) revealed in an interview that during recording of Transformers: Prime, he and the cast are given the scripts and "a couple of days [...] to figure out where the story is going".

Tyler stated that when he approached to perform the music for the series, they wanted it to be "cinematic, thematic [and feature] classic scores, similar to Star Wars."

[31] Reruns of the series began airing on The CW as part of the Vortexx block on December 8, 2012, making Prime the first Hasbro Studios animated production to appear on United States terrestrial television.

Stower described the first season as "a very slow burn, [with] its eventual payoff [being] incredibly anticlimactic" and that in their attempt to focus on the Transformers' mythology, the writers "forgot to craft three-dimensional, likable characters".

However, he concluded that the show did live up to its promise of an epic tale late in its run and reacted positively to Prime's portrayal of Ratchet and Starscream.

He praised the show for creating fully formed, relatable characters, well-done action sequences, serious-minded storylines and voice acting, singling out Peter Cullen (Optimus Prime), Jeffrey Combs (Ratchet) and Frank Welker's (Megatron) performances.

He concluded the review saying that the series "accomplishes its goals, delivering plenty of fun and action, while also incorporating darker and more complex moments that older viewers can appreciate".

[56] Brian Lowry of Variety said that Transformers: Prime is "unexpectedly sharp" and better than the movies, adding that the show's CGI animation is well-suited for rendering shiny robots and "their vehicular alter egos"; he ended the review by saying that while "there's nothing more than meets the eye here, [..] what does appear is plenty entertaining".

[63] Ruckus Mobile Media partnered with Hasbro to deliver Transformers: Prime innovative storybook apps for Android, and iOS (iPad, iPhone, iPod Touch) systems.

The app was meant to deliver immersive reading experiences with interactive storytelling including title specific activities, coloring and read-and-record functions.

The series introduces a new cast of characters who help Bumblebee in his mission, including Strongarm, Sideswipe, Grimlock, Fixit, and the humans Denny Clay and his son Russell.