A special science unit is set up by the US government, with the seemingly uninteresting goal of researching plants. However, it is revealed that their true goal is to track down mysterious beings known as 'Unknowns' which have mysteriously appeared. It is then discovered that the Unknowns were created by the government themselves at Area 51. They were freed by a rogue agent who revealed himself to be a vampire-like villain named Sepiroth. Near the end of the season, the government learns that the team has discovered the origin of the Unknowns and seek to shut the unit down. Sepiroth infiltrates the lab disguised as an agent of the FBI. He transforms Sophie into a similar being to himself before he is decapitated by Matt with a fire escape axe. Sophie then abandons the unit because of her condition.
Sophie returns with her mind having been warped by her new powers. She allies herself with an Aztec priest who is seeking immortality and together, they free more supernatural beings called 'Abnormals.' Matt repeatedly attempts to break through to her, but it only drives her more insane. The team is also joined by Samantha's long lost daughter Ally, who assists them in battling the far more powerful Abnormals. Sophie later turns on the priest after he is trapped in a mirror, which she smashes. She is then confronted by the team and vampire hunter Snipe. Snipe is determined to slay Sophie, but Matt is convinced that he can reach her before she opens the rift between Earth and the world of Abnormals. Snipe pursues him and prepares to finish Sophie. However, she is left vunerable after Matt breaks through to her and she then allows herself to be staked by Snipe. Snipe and Matt struggle while Samantha retrieves her gun and fatally shoots Snipe, saving Matt.
Season 2 also introduces the important character of Lucien, a mysterious man who has some mystery connection to the Abnormals and a history with Samantha. Although only a minor character here, he would go on to play a pivotal role in both Seasons 3 and 4.
In spite of Sophie's demise, the Abnormals continue to appear in our world. The group learns of Lucien's meddling with the two worlds and that he is the one channeling dark energy to free the Abnormals. They team up with Sam's old partner, Harry, who is working undercover to bring down a mysterious criminal related to several high profile murders. They find that Lucien is the mystery person who is forming a cult using people's fear of the Abnormals, and leading those members to kill people for him. The group have a final confrontation in a warehouse, where Lucien emits incredibly powerful bursts of energy before Harry stabs him with a special dagger and Ally shoots him.
The cult re-emerges and starts killing again. The team attempt to locate the cult's leader and find a man referred to as Rameses. Rameses is captured, but the cult is continued by a Galileo. Galileo allows himself to die in front of a large cross, from which Rameses draws power and escapes. After they track him down, the team learns that he is still answering to Lucien. Harry then shoots and kills Rameses, increasing Sam's suspicions. She confronts Harry and he reveals that he is possessed by Lucien's spirit, having connected to him after his death in the warehouse. Harry/Lucien flees to Cairo, where he is meeting with a Sheikh in hopes of increasing his power. The team follows him and Harry/Lucien burns up Harry's body in an attempt to transfer his life to Ally. Matt, realising what is happening, punches the Sheikh, enticing him to slash Matt across the chest and stomach as a reflex. Matt then throws himself into the way of Lucien's spirit as it flies towards Ally, thus absorbing it. Matt then dies as he drags Lucien's spirit into the afterlife, finally defeating him.
The fifth and final season introduces a new group of antagonists; the Divine. They are angel-like creatures that live in another dimension which resembles Hell, referred to as the Nether Realm. Lucien's meddling has attracted their unwanted attention and are led by the mysterious Fallen, a hooded figure who can also manipulate the remaining Abnormals.
Early in the season, Matt is ressurected from the dead and returns to the team to face the Divine as they begin to cross into our world and spread chaos. The team's primary goal is to uncover the identity of the Fallen and take him down. Sam begins to suspect that Matt is the Fallen, as the Divine first appeared shortly after his return. Meanwhile, Matt and Ally confess their love for each other, with him admitting that she was the sole reason he allowed himself to die. However, after an incident involving the Divine, Ally begins to doubt herself and share her mother's suspicions. She begins to date Neil, who works at the local mall, and she and Matt grow further apart. On the night that she ready to profess her love to Neil, however, he kidnaps her and reveals himself as the true Fallen. Before he can carry her back to the Nether Realm and marry her to become mortal, Neil is intercepted by the team and Matt drags him into the Nether Realm.
The two fight in the Nether Realm as it begins to collapse around them. As Matt jumps towards the collapsing gate, Neil leaps after him and they dangle above a lava pit. Neil finally buckles and plunges to his final demise while Matt escapes back through the portal just before it is completely disabled, forever severing the link between our world and the world of the Divine. Matt and Ally rekindle their relationship and drive away together while Sam wonders what else the universe holds before looking up at the stars.
The ending of the fifth season gave many fans the impression that a sixth season involving aliens would be produced. However, no deal was struck or even reported and, despite online petitions by devoted fans, the show was officially cancelled by the network in early 2019.