The departure of One Life to Live ended a 62-year history of daytime television soap operas taped in New York which started in 1950 with the CBS's daytime drama The First Hundred Years.

One Life to Live enjoyed fair-to-middling ratings in the 1960s, but rose rapidly as it entered the 1970s, along with the rest of ABC's daytime lineup. Matters greatly improved for One Life to Live in 1972, when CBS relocated Edge of Night in response to packager Procter and Gamble's demands. The four-year-old show topped the ratings for the first time over CBS' declining Secret Storm, and later, the game Hollywood's Talking, which ran for only 13 weeks.

ABC cemented its reputation as a youth-oriented network in daytime with the addition of One Life to Live to its schedule, with much of the rest of its lineup consisting of soap operas like Dark Shadows, sitcom reruns, and game shows packaged by Chuck Barris. One Life to Live replaced the short-lived Baby Game, in a three-way shuffle with Dark Shadows and Dating Game. The network placed the new serial at 3:30 PM EST, against CBS's established hit Edge of Night and the popular NBC game You Don't Say. Despite the tough competition, the intense tone of the plot and strong characters allowed the show to get a leg up on You Don't Say, wearing that game down to the point of its cancellation in September 1969; NBC replaced the Tom Kennedy-hosted game in that time slot with three unsuccessful serials: Bright Promise, Return to Peyton Place, and How to Survive a Marriage.

Throughout the show's history, the plot lines of One Life to Live have been established as existing in the same fictional universe as other ABC-owned daytime series, in particular Agnes Nixon's All My Children, which premiered in 1970. As noted from time to time in both series, fictional Pine Valley—the setting of All My Children—is located in Pennsylvania near One Life to Live's Llanview. Over the years, many characters have crossed over from one series to another in both short appearances and extended runs. As early as 1968, General Hospital's Dr. Steve Hardy appeared in Llanview to consult on Meredith Lord Wolek's blood disease as a means to lead General Hospital viewers to the new series; similarly, One Life to Live's Dr. Larry Wolek visited All My Children shortly after its premiere in 1970.

One Life to Live heavily focuses on the members and relationships of the Lord family. Actress Erika Slezak began portraying the series' central protagonist Victoria "Viki" Lord in March 1971 and played the character continuously for the rest of the show's run on ABC Daytime, winning a record six Daytime Emmy Awards for the role. In 2002, the series won an Emmy for Outstanding Drama Series. One Life to Live was the last American daytime soap opera taped in New York City.

By 1975, NBC became a serious player in that time slot for the first time in over five years when it expanded its strong soap opera Another World to an hour, with its second half occupying the 3:30 timeslot. One Life to Live lost a substantial audience share, but its lead-in, General Hospital, experienced even worse losses. ABC then expanded both One Life to Live and General Hospital to 45 minutes, with each composing half of a 90-minute block between 2:30 PM and 4 PM. Beginning on July 26, 1976, One Life to Live assumed the first position, at 2:30. ABC bet its hopes on viewers staying tuned past the half hour, making them unlikely to switch channels to Another World and All in the Family reruns on CBS (or Match Game in the case of General Hospital fans). This approach showed some promise, until November 7, 1977, when CBS expanded Guiding Light to an hour. As One Life to Live struggled, its neighbor General Hospital was in danger of cancellation after a 15-year run. ABC then expanded One Life to Live to an hour on January 16, 1978, in the 2:00 PM timeslot (with General Hospital following at 3:00 PM); The $20,000 Pyramid was moved to noon for the rest of its ABC run to make room.

General Hospital rose rapidly to the top spot in the Nielsen ratings by 1979. As for One Life to Live, from its tenth birthday onward, its competitors declined in popularity. Search for Tomorrow, for instance, spent its last several months on CBS against the last half of One Life to Live. Its replacement, Capitol, did little better, and after its cancellation, CBS aligned As the World Turns against One Life to Live and Another World, a configuration that stayed in place until Another World's cancellation in 1999. The 1980s saw One Life to Live reach the height of its popularity, with an estimate of 9 million viewers early in the decade. The show typically ranked between the second and the fourth position in the 1980s.

Since 1991, One Life to Live returned to the middle of the pack, but its numbers declined, in Common with all other soap operas. By the decade's end, the show rested near the bottom of the ratings pack, and it continued to hover around the lower reaches of the weekly ratings throughout the 2000s in terms of total number of viewers; however, the show tended to rank in the mid-range for the target demographic of women aged 18–49, often higher than sister show All My Children. During the 2000s (decade), One Life to Live ran about even with As the World Turns, with NBC's Another World replacement Passions trailing significantly.

In 1993, the series won its first GLAAD Media Award for its groundbreaking storyline on homosexuality and intolerance featuring newcomer Ryan Phillippe as Billy Douglas, a teenager who amidst scandal confides his homosexuality in Andrew Carpenter, played by Wortham Krimmer. The story arc also included an on-air ceremony for the NAMES Project AIDS Memorial Quilt. In 2005, the series was awarded another GLAAD Media Award for its coverage of LGBT issues in the 2004 coming out storyline of gay character Mark Solomon (Matt Cavenaugh). One Life to Live won the same award again in 2010 for a well-publicized storyline in which police officer Oliver Fish comes out and reunites with his former college boyfriend and medical school student Kyle Lewis.

In 1999, Daytime Emmy Award-winner Linda Dano returned to One Life to Live as Gretel Cummings, a character she had previously played on the series from 1978 to 1980. In a 2000 move of network synergy designed to "entice viewers to tune into soap operas that they might not have usually watched," then-President of ABC Daytime Angela Shapiro orchestrated Dano's concurrent appearance as Gretel on the three other ABC daytime dramas at the time — All My Children, General Hospital, and Port Charles — in an extended crossover storyline which was the first time a daytime character had ever appeared on four series. Gretel's search for the child she had given up for adoption takes her to All My Children, where she discovers in 2000 that her own birth mother is Pine Valley's Myrtle Fargate. Following clues to Port Charles and General Hospital, Gretel finally finds her daughter back in Llanview on One Life to Live: Skye Chandler, herself a former All My Children character who had relocated to One Life to Live in 1999. Skye's adopted All My Children father Adam Chandler appears on One Life to Live in 2001, and Gretel initially identifies Skye's biological father as Alan Quartermaine of General Hospital. Both women subsequently appear on that series, with Skye moving to General Hospital full-time in 2001 and Gretel returning to One Life to Live until 2004, making some appearances on General Hospital later in 2002 and 2003.

In 2002, the popularity of antihero Todd Manning (Roger Howarth) prompted ABC to market a rag doll of the character, complete with his signature scar. First offered for sale on April 29, 2002, the doll was pulled on May 7, 2002, after a backlash begun when The Jack Myers Report "harshly criticized the network's judgment" on creating and releasing a doll based on Manning, a character who had notably been convicted of rape in 1993. The New York Times later quoted then-ABC President Angela Shapiro stating, "I was insensitive and take total responsibility for it. I should have been sensitive to the history of the character and I wasn't."

A December 30, 2003, visit by One Life to Live's Paul Cramer to his estranged secret wife Babe Carey on All My Children ultimately leads to an extensive 2004 "baby switch" storyline which features crossovers of over 20 characters between the two series. With his sister Kelly desperate for a child to save her marriage after miscarrying her own, Paul finds himself delivering the babies of both Babe and her friend Bianca Montgomery during a rainstorm and subsequent flood in nearby Pine Valley on March 24, 2004. Paul stages a crash with his MEDEVAC helicopter; he takes Babe's son for Kelly, gives Bianca's daughter to Babe, and tells Bianca that her baby had died in the accident. Unaware of the child's origins, Kelly brings Babe's infant back to Llanview, passing him off as her child with her husband Kevin Buchanan. Months later, Babe discovers that her daughter is really the grieving Bianca's, but remains silent and allows Paul to manipulate her. Meanwhile, a devastated Kelly discovers that Paul had stolen her son from his mother and, desperate for cash, he blackmails Kelly by threatening to reveal the secret to Kevin. Bianca's daughter is returned to her for Christmas 2004, and once Kevin learns the truth, he and Kelly return Babe's son as well in 2005.

Shortly after receiving a March 2005 GLAAD Media Award for its coverage of LGBT issues, One Life to Live was met with criticism when married district attorney Daniel Colson (Mark Dobies) was revealed to have murdered two people to cover up the fact that he was secretly gay. GLAAD itself criticized the storyline "for reinforcing the idea that being gay is something to be ashamed of," while TV Guide noted "It's hard to disagree with those who say that's a lousy representation of gay folks." Executive Producer Frank Valentini defended the story, saying, "This is a story about the harsher side of intolerance and about one man not being true to himself. There are going to be meaningful, frank discussions that come out of this." Then-head Writer Dena Higley explained, "The number one rule of soap opera is never cut drama. Daniel being gay and keeping that a secret is a dramatic story."

One Life to Live celebrated its 40th anniversary in July 2008 with the return of several former cast members and by revisiting notable plot lines from its past. "Deceased" characters and even creator Agnes Nixon appeared in a storyline in which Slezak's Viki dies and visits Heaven, an homage to Viki's 1987 heavenly trip. Daytime Emmy-nominee Andrea Evans and others returned for a tribute to Tina Lord's famous 1987 plunge over the Iguazu Falls and the 1990 royal wedding in fictional Mendorra. And like the 1988 Old West storyline in which the character Clint Buchanan steps back 100 years in the past, on July 21, 2008, Robert S. Woods began an extended storyline in which his character Bo Buchanan finds himself transplanted back into his own past—specifically 1968, the year of the series' inception—witnessing his family's back-story unfold. Soap Opera Digest subsequently named One Life to Live their "Best Show" of 2008, calling it "the year's most compelling" series and citing a myriad of story lines the magazine found "heartbreaking," "stunning," and "gripping," as well as complimenting its risk-taking and "diverse and talented" cast.

In June 2009, Actress Patricia Mauceri (a performer on the series since 1995) was replaced in her role as Latin matriarch Carlotta Vega, reportedly after voicing personal religious objections to a planned storyline in which Carlotta would be supportive of a gay relationship.

The 2009-2010 season was a particularly difficult year for One Life to Live. During the week of June 28, 2010, the show ranked last among all soap operas with 2.1 million viewers, compared to 2.3 million for As the World Turns. As One Life to Live entered the 2010-2011 season, ratings improved, but not enough to prevent ABC from cancelling the program on April 14, 2011. After the cancellation announcement, One Life to Live began to surpass General Hospital in total number of viewers, but General Hospital continued to dominate One Life to Live in several specific categories, most notably the key demographic of women between 18 and 49 years old, usually prioritized by daytime networks. By November 2011, One Life to Live had dethroned General Hospital in every category. Overall, One Life to Live was the third highest rated program among the five remaining soap operas in its last season, trailing The Young and the Restless and The Bold and the Beautiful, but ahead of General Hospital and Days of Our Lives. The show averaged 2.6 million viewers on a daily basis during its final weeks. Its final episode on January 13, 2012 drew more than 3.8 millions viewers, one of the highest ratings in the history of soap opera finales.

On December 1, 2011, two weeks after One Life to Live finished taping its final scenes, ABC confirmed that former executive Producer Frank Valentini and head Writer Ron Carlivati would assume the same roles on General Hospital effective January 9, 2012.

While One Life to Live was off the air from February 2012 to March 2013, the characters of Todd Manning, Starr Manning and John McBain moved to the setting of General Hospital, Port Charles, New York.

Starting July 15, 2013, OWN began a 10 week trial run of both One Life to Live and All My Children on its daytime lineup. Episodes of One Life to Live are broadcast at 1:30 P.M., following All My Children which airs at 1:00 P.M., Mondays through Thursdays.