General Hospital was created by husband-and-wife soap writers Frank and Doris Hursley, and is set in the fictional city of Port Charles, New York. It was only the second soap to air on ABC (after the short-lived Road to Reality, which aired for several months during the 1960-61 season). Currently taped at The Prospect Studios, General Hospital originally aired for a half-hour. The series was expanded from 30 minutes to 45 minutes on July 23, 1976, and then to a full hour on November 7, 1977. It holds the record for most Daytime Emmy Awards for Outstanding Drama Series, with 10 wins. In 1964, a sister soap was created for General Hospital, The Young Marrieds. It ran for only two years, and was cancelled due to low ratings in 1966. General Hospital also spawned a prime time spin-off with the same name in the United Kingdom from 1972 to 1979, as well as the daytime series Port Charles (1997–2003) and the prime time spin-off General Hospital: Night Shift (2007–2008) in the United States.

On September 18, 2009, when Guiding Light aired its final episode on CBS Television, General Hospital became the second longest running American soap opera currently on air, after As the World Turns. On December 8, 2009, CBS announced that they were cancelling As the World Turns and its final episode will air on September 17, 2010. General Hospital will then become the longest-running daytime soap opera still featured on American television, having aired continuously since April 1, 1963, and the British soap opera Coronation Street will be the world's longest-lived soap opera currently airing on television, having been on air since 1960.

Launched in 1963, the first stories were mainly set at General Hospital in an unnamed mid-sized Eastern city (the name of the city, Port Charles, would not be mentioned until the 1970s), revolving around Dr. Steve Hardy (John Beradino) and his friend, Nurse Jessie Brewer (Emily McLaughlin). Steve was Chief of Internal Medicine on the hospital's seventh floor and dedicated his life to healing and caring for the sick, ably assisted by Nurse Jessie. Jessie's turbulent marriage to the much-younger Dr. Phil Brewer (originally portrayed by Roy Thinnes; lastly by Martin West) was the center of many early storylines.

The 1981 wedding of Luke and Laura, played by Anthony Geary and Genie Francis, was the most watched event in daytime serial history. Luke and Laura appeared on the cover of Time Magazine for their breakthrough marriage!

During the 1980s the series featured several high-profile action, adventure, and some science fiction based story lines. Location shooting at sites including Mt. Rushmore in South Dakota; Niagara Falls; Grand Ole Opry in Nashville, Tennessee; Atlantic City, New Jersey; Big Bear and Avalon (Catalina Island), California; and San Antonio, Texas are just some that propelled the story.

In the 1990s, General Hospital entered a transitional phase as the action/adventure storylines of the 1980s became less popular. The show gained critical acclaim for its sensitive handling of social issues, most notable of which were the heart transplant storyline which involved the death of eight-year-old BJ Jones (daughter of Dr. Tony Jones and R.N. Bobbie Spencer) in a bus crash and the subsequent donation of her heart to her dying cousin Maxie Jones. Shortly afterwards, Monica Quartermaine (Leslie Charleson) began a long battle with breast cancer, which led to her adopting Emily Quartermaine, a young girl who had been orphaned when her mother died of breast cancer. Her adopted daughter was later murdered by an unknown killer, leaving Dr. Monica Quartermanine heartbroken. GH was also praised for yet another storyline in the form of the beautiful but tragic love story of teenagers Stone Cates (Michael Sutton) and Robin Scorpio (Kimberly McCullough). After a struggle that lasted throughout most of 1995, Stone died from AIDS at the age of 19 and his death was followed by storylines in which 17 year old Robin had to deal with being HIV-positive as a result of her and Stone's relationship. The storyline got Sutton a Daytime Emmy nomination for Outstanding Supporting Actor and won McCullough an Outstanding Younger Actress award. ABC featured an "Afterschool Special" revolving around the AIDS story.

On Saturday, December 14, 1996, General Hospital aired its one of three primetime episodes, General Hospital: Twist of Fate, which picked up where that Friday's episode had left off. The special centered around Laura's supposed death at the hands of Stefan Cassadine.

The series' 11,000th episode aired on February 20, 2006.

On April 23, 2009, General Hospital became ABC's first regular daytime drama to be taped and broadcast in high definition, though the 2008 season of its primetime spin-off General Hospital: Night Shift was in high definition. This is the second daytime drama to move to high definition after CBS's The Young and the Restless.

On February 23, 2010, the series aired its 12,000th episode.