Gregory House was born on June 11, 1959 to John and Blythe House (R. Lee Ermey and Diane Baker). House is a "military brat"; his father served as a Marine Corps pilot and transferred often to other bases during House's childhood. One place in which his father was stationed was Egypt, where House developed a fascination with archaeology and treasure-hunting, an interest which led him to keep his treasure-hunting tools well into his adulthood. Another station was Japan, where, at age 14, House discovered his vocation after witnessing the respect given to a buraku doctor who solved a case no other doctor could. House loves his mother but hates his father, who he claims has an "insane moral compass", and deliberately attempts to avoid both parents. At one point, House tells a story of his parents leaving him with his grandmother, or "oma" (Dutch for grandmother), whose punishments constituted abuse. However, he later confesses that it was his father who abused him. Due to his father abusing him, House never believed that John House was his biological father; at the age of 12, he deduced that a friend of his family with the same birthmark was his real father. In the season 5 episode "Birthmarks", House discovers that this was true, after he ordered a DNA test that compared and matched his DNA against John's.

House initially attended Johns Hopkins University as an undergraduate, studying medicine at the Johns Hopkins Medical School. He was up for a scholarship at the Mayo Clinic, however, during his medical education, he was caught cheating by a co-student named Philip Weber who ultimately got him expelled. He then attended the University of Michigan in order to finish his medical study. In Michigan, while working at the bookstore, he met his future boss Lisa Cuddy (Lisa Edelstein) with whom he shared (in his words) "a passionate yet forgetful" one-night stand. During a medical convention in New Orleans that he attended shortly after graduating medical school, House first saw his eventual friend Dr James Wilson (Robert Sean Leonard) among a "sea of boring people" clutching a package. House deduced that it contained divorce papers. While at a bar, Wilson accidentally broke an antique mirror and started a bar fight when a man, repeatedly played "Leave A Tender Moment Alone" by Billy Joel to the frustration of Wilson who indeed was going through his first divorce at the time. Out of interest, House bailed him out and hired an attorney to clear his name, thus starting their professional and personal relationship.

Approximately ten years before the series began, House entered into a relationship with Stacy Warner (Sela Ward), a constitutional lawyer, after she shot him during a "Lawyers vs. Doctors" paintball match. Five years later, during a game of golf, he suffered an infarction in his right leg which went misdiagnosed for three days due to doctors' concerns that he was exhibiting drug-seeking behavior. (House eventually diagnosed the infarction himself.) An aneurysm in his thigh had clotted leading to an infarction and causing his quadriceps muscle to become necrotic. House had the dead muscle bypassed in order to restore circulation to the remainder of his leg, risking organ failure and cardiac arrest. He was willing to endure excruciating post-operative pain to retain the use of his leg. However, after he was put into a chemically induced coma to sleep through the worst of the pain, Warner, House's medical proxy, acted against his wishes and authorized a safer surgical middle-ground procedure between amputation and a bypass by removing just the dead muscle. This resulted in the partial loss of use in his leg and left House with a lesser, but still serious, level of pain for the rest of his life. House could not forgive Stacy for making the decision and this was eventually the reason Stacy left him. House now suffers chronic pain in his thigh and uses a cane to aid his walking. He also frequently takes Vicodin to relieve his pain. House does however break his addiction with psychiatric help - after a near overdose. When Warner makes her first appearance in the series she is married to a high school guidance counselor named Mark Warner. Although she and House reunite briefly for some hot, passionate sex during the second season, House eventually tells Warner to go back to her husband, devastating her.

At the beginning of season three, House temporarily regains his ability to walk and run after receiving ketamine treatment. However, the chronic pain in his leg comes back and House takes painkillers and uses his cane once again. The other doctors speculate that his cane and opiate re-usage are due to his psychological tendencies. During season five, House once again regains his ability to walk without pain after taking methadone, but soon stops after nearly killing a patient due to a medical error. At the start of season six, House stops taking pain medications and finds other ways to deal with his pain. One of these includes cooking, upon which "Thirteen" and Wilson discover that House is a great cook, attributing this to House thinking of ingredients in terms of chemistry.

-Dr. House Interview