Eleven months after driving his car into Cuddy's house, three of which were spent on the run and the other eight in prison, House goes before the parole board and learns he has only five days left before he is released. A local prison gang leader then demands twenty Vicodin pills as an "exit tax." As House scrambles to pay up, he tries to treat another inmate (Sebastian Sozzi) with joint pain while turning Dr. Jessica Adams (Odette Annable) to his point of view.

Final diagnosis: Mastocytosis

After two further months in prison, House is released early after an urgent request by Foreman, who is the new dean of medicine. Things have changed: House has lost his office and his team, while Wilson is mad at him and their friendship is tested. What he has gained is a new "team"—Dr. Chi Park (Charlyne Yi), a smart, young timid resident—and a new case: a set of donor lungs that are failing, threatening the life of Wilson's patient (Liza Snyder).

Final diagnosis: Eosinophilic pneumonitis

When a man (Wentworth Miller) collapses after making a million dollar donation, Dr. Park believes his extreme altruism may indicate a neurological disorder, while House sees a way to fund the rebuilding of his old team back together. Meanwhile, Dr. Adams volunteers her services to the department while looking for a new career, and Thirteen (Olivia Wilde) returns to House only to say goodbye again.

Final diagnosis: Plummer's disease

A CEO (Michael Nouri) begins experiencing vision problems days before a major business decision, and House sees it as the perfect way to fund the department through a little blackmail. Meanwhile, Dr. Park prepares for her disciplinary hearing, and Dr. Adams reveals something about her past.

Final diagnosis: Hyperviscosity syndrome secondary to rheumatoid arthritis

Chase and Taub return to the team, as the team takes the case of a man (Jamie Bamber) who suffers heart problems while having an affair. When his health worsens, he decides to confess all his past sins to clear his conscience, which compromises his treatment. Meanwhile, House becomes obsessed with finding out if Taub's two daughters are, in fact, actually Taub's.

A teenage boy (Harrison Thomas) attempting to follow in his deceased father's footsteps suffers paralysis at a party. As the team searches for answers, they discover a family secret that threatens the young boy's treatment. Meanwhile, House searches for a valid reason to attend a boxing match in Atlantic City, and Taub must decide whether to allow his ex-wife to move away, taking his daughter with her.

The team takes the case of a teenage girl (Madison Davenport) presenting with anaphylaxis but soon discover that her condition is far more serious when it is discovered that she is pregnant but claiming to be a virgin. House goes to an AA meeting to meet a man whose 4-year-old son has died and his wife divorced him. Determined to find out what happened to the boy, House bribes the cemetery owner to examine the remains of the boy, even as Foreman instructs him to keep on the case.

The team takes the case of a prosecutor (Vincent Spano) who suffers an apparent heart attack during a case, but when they discover a huge hidden cache of weapons in his home, they must decide whether it's overprotectiveness or paranoia. Meanwhile, Taub decides to assist Foreman in his romantic affairs, and Park eventually starts to realize she needs to open up herself to the other people.

A man suffering from early-onset familial Alzheimer's disease (Ivo Nandi) begins vomiting, and is admitted to the hospital, with his wife (Melanie Lynskey) taking care of him. He soon develops aggression and language loss, but the team find it difficult to distinguish his new symptoms from his Alzheimer's. Meanwhile, House and Wilson keep betting on what is causing a woman's apparent asexuality and Foreman debates whether or not he should petition House's parole officer to remove his ankle monitor early.

Final diagnosis: Reye's syndrome

The team takes the case of a teenage girl (Bridgit Mendler) who begins bleeding from her ear during an exam. She is thriving without parental influence and lives alone in a house, but Adams debates calling Social Services anyway. However, when her estranged mother shows up, the girl loses her right to consent to treatment. Meanwhile, Taub tries to connect with his daughters, and House tries to blackmail Foreman on his relationship with a married woman.

House and his team face a disciplinary hearing with Dr. Cofield (Jeffrey Wright) after a chemistry teacher (David Anders) is admitted to the hospital with paralysis. But things turn bad when in a fit of psychosis and violence, the patient stabs Chase, ultimately forcing the team into a race against time as they battle to keep Chase alive in the ER. As the patient is going to be transferred, House realizes his syndrome and informs his wife. As he is on the hearing with Dr. Cofield, he is prepared to send House to prison again, but the wife of the patient arrives and thanks him for his correct treatment. Dr. Cofield sets him free, but House berates him for his cowardice as it was obvious that he would have been arrested, so he let him loose to avoid media attention.

Chase's near-death experience has him questioning if he should return to House's team. Meanwhile, he takes the case of a clinic patient (Julie Mond), a nun on the verge of making her vows, when she begins vomiting and exhibiting neurological symptoms. During the course of her treatment, he develops feelings for her which compromise his objectivity. In a subplot, House subjects Taub to a series of prankish 'ambushes' in order to prove to him, in light of Chase's stabbing, that nobody can fully prepare for the unexpected.

A marriage counselor (Jake Weber) collapses during a speaking engagement, when it is discovered that, in addition to vision and liver problems, his low testosterone levels are affecting his marriage and career for the better. Meanwhile, House's wife returns to prepare House for their meeting with Homeland Security for her green card, as the team vies for a position as House's second-in-command.

An independent blind man (Michael B. Jordan) is admitted to the hospital after suffering auditory hallucinations, and soon begins coughing up blood. However, his treatment could leave him more disabled than before. Meanwhile, House’s mother (Diane Baker) surprises him at Princeton Plainsboro to tell him about a new relationship with his old doctor (Billy Connolly), who might be his biological father.

Final diagnosis: Mucormycosis

Absent: Omar Epps as Eric Foreman

A soldier (Arlen Escarpeta) returning from overseas, accused of treason after releasing a video showing soldiers killing civilians, collapses and is taken to Princeton-Plainsboro. He soon refuses treatment until he has the opportunity to explain his decision to the masses. Meanwhile, Adams and the team believe House is seriously ill.

House and the team take the case of a minor league hockey player (Greg Finley) who began coughing up blood after a fight on the ice. Meanwhile, House reveals to Wilson that he might have an 11-year-old son, and Park moves in with Chase after a fight with her mother.

Final diagnosis: Miller Fisher syndrome

A man (Kevin Christy) is admitted to the hospital when he begins crying blood, but the team suspects a neurological component when they meet his "girlfriend"—a very lifelike sex doll with whom he's fallen in love, and he also admits why. Meanwhile, House confronts his insecurities when his hooker/companion decides to leave him.

Final diagnosis: Primary amoebic meningoencephalitis

A boy (Riley Lennon Nice) is admitted to the hospital after nightmares about being choked led to breathing problems. His mother tries to balance the medical diagnoses of the team with his Hmong grandfather's belief that the boy is possessed. Meanwhile, Chase and Park debate the meaning of their sex dreams, Dominika discovers House's deception, and Wilson tells House that he (Wilson) has cancer (Stage 2 Thymoma).

A six-year-old girl (Rachel Eggleston) with a rare genetic disorder (Ataxia Telangiectasia) is admitted to the hospital after suffering a nosebleed and losing consciousness. Foreman has the team consult with her mother (Jessica Collins) who is also an expert in her daughter's condition. Meanwhile, Wilson decides on a radical and potentially fatal course of treatment for his cancer, which House agrees to administer himself.

When the hospital's coroner (Jamie Elman) begins slicing his own scalp open, he is admitted but will only accept medical care personally decided on by House. However, House is unreachable as he and Wilson embark on a journey for Wilson to forget his upcoming scan and let loose. Meanwhile, a conversation with the patient leads Chase to re-evaluate his career.

A college student (Skylar Astin) is admitted with dizziness and nosebleeds but the team soon discovers that he hears his dead brother's voice, and they must try to decide which of his symptoms are psychological in nature. Meanwhile, House and Wilson deal with the fact that the cancer treatment failed; Wilson decides to stop further treatment and die with dignity, while House's pranks inadvertently violate his court probation, which leaves him inevitably facing incarceration well past Wilson's final months.

Final diagnosis: Persistent stapedial artery

After failing to get out of his upcoming jail time, House disappears and his team, along with Wilson and Thirteen (Olivia Wilde), are unable to locate him. He awakens in a burning building after shooting heroin with his former patient (James LeGros). With his life crumbling around him, House hallucinates people from his past (Braugher, Dudek, Morrison, Penn, Tamblyn, Ward) as he decides whether his life is worth living anymore. Believing House dead, members of the staff and family pay funeral tributes to him, including Wilson who denounces his selfishness until getting an odd text message---luring him to meet a very alive House, who faked his death to remake his life. Back at PPTH, Foreman settles into Cuddy's old job, and Chase succeeds House as director of diagnostic medicine, with Adams and Park as his new team. Meanwhile, Taub dines with Rachel, Ruby, and his daughters, and a re-married Cameron has become a mother and chief of a Chicago emergency room. Mounting motorcycles together, House offers to help make Wilson's last months of life liveable.