Two years after the events of ObsCure, the survivors have had to move on with their lives. Shannon and Kenny are now enrolled in the nearby Fallcreek University, while Stan is making ends meet as a pizza delivery boy. Stan and Kenny now have to take medication to prevent the effects of the plantation from infecting their bodies while Shannon has been able to adapt to the changes.

As the story begins, a new drug created from a strange flower is quickly spreading its influence over the University's populace. Soon enough, a small group of students along with the Leafmore High survivors have to face a horde of mutants and stop the spread of contagion before the situation becomes critical.

Shannon and Cory stumble upon a monster.

The students meet a scientist Richard James, who is immersed in the biology of the scientific black spores, and aids the player several times.

The flower spore spread through the campus and affects the nearby hospital. Mei, who gets a call from her twin sister Jun, goes with Sven to rescue her, but fails when she is killed by an unknown monster. The player eventually switches to Corey, and he finds Shannon and her brother Kenny, who is badly injured inside by the black spores and turns into a monster with huge arms.

When Sven and Corey meet up at a warehouse with the others, Kenny in his monstrous form appears and kills Mei, thus distressing Corey. Stan meets with the surviving group and drives them away, until he crashes off a cliff into an unknown forest. Eventually, the monstrous Kenny strikes again, while Corey and Shannon defeat him by making him fall into a seemingly endless pit in a warehouse.

As the game progresses, Stan and Shannon get closer together.

While Shannon and Stan find a place to take refuge, Amy and Sven explore and are ambushed by an unknown man carrying a chainsaw, with a disfigured face. The disfigured man fights Sven while Amy escapes.

When they find Sven impaled by a chainsaw by the disfigured man at an abandoned house, Stan and Shannon chase after the disfigured man, leading to the Ruins of the School from the original game and to find out a horrifying, living tree with huge moving branches. The huge tree was actually the mutated remains of Leonard Friedman (from "Obscure 1") and the disfigured man was his son. In the past, Friedman had injected himself with a strain of virus that mutated him and transferred (through his genes) onto his son, Jedidiah, causing the horrifying features of the man. Stan and Corey kill the Friedman tree by sawing off the main parts of the huge moving branches, while Corey finishes off the disfigured son by slicing him with the chainsaw.

When the pair return, they find Richard James and an ambulance carrying Amy pregnant with a mutation. Stan and Corey find out that she was raped by Kenny in his monstrous form. The ambulances take Stan, Shannon, Amy, and Corey away, but they crash at a bridge after going through a dark aura of spores under a bridge. Stan and Shannon try to find out what Richard's new pickup point is and try to reach there, while Corey goes to rescue Amy.

When Shannon and Stan reach the new destination point, they find Corey lying on the ground with surprisingly alive monster Kenny, and Richard James taking off with Amy in a helicopter. Kenny had planned to unite with Corey because he had taken "everything precious" to him. Corey, feeling desolate states that Mei was the only one that he cared about, and commits suicide by shooting himself in the head. Stan and Shannon, the only ones left fight Kenny and kill him by crushing him with a huge floating platform on the ceiling.

As Kenny lies dying by the crushing platform, he pleads to Shannon to take care of his child living in Amy. Shannon swears that she will not let it live. Meanwhile, the helicopter containing Amy and Richard suddenly fill up with an aura of dark spores, and the helicopter explodes. Finally the end, Stan asks Shannon what to do next. As a cloud of black spores rapidly spread all over the area, she replies strongly that she will continue and cut all family ties.