The series was created by husband-and-wife team Ted Corday and Betty Corday, combining the 'hospital soap' concept with a family-centered drama about a family of doctors, including one working in a mental hospital.

Co-creator and original executive producer Ted Corday died of cancer in 1966, only eight months after the show premiered, after which his widow Betty Corday took over as executive producer.

Irna Phillips, the creator of Another World, As the World Turns, and Guiding Light, served as a story editor during the show's early years, and many of its earliest storylines were written by William J. Bell, who later left in 1975 to focus on The Young and the Restless, which he created for CBS.

Daily episodes were expanded from 30 minutes to 60 minutes on April 21, 1975, following the lead of fellow NBC soap Another World, which had become the first hour-long TV soap 3½ months earlier.

The January 12, 1976 cover of Time magazine featured Days of Our Lives actors Bill Hayes and Susan Seaforth Hayes, making them the only daytime soap actors ever to appear on the magazine's cover; the couple met on the series in 1970 and married in real life in 1974.

The 1984 'Gone with the Wind' storyline, in which Hope and Bo Brady hide out on a Southern plantation dressed as Scarlett O'Hara and Rhett Butler, was devised specifically to keep viewers tuned in while rival network ABC's soaps were preempted by the 1984 Summer Olympics.

The show has been parodied by sketch comedy series SCTV (as 'The Days of the Week') and by the sitcom Friends, with several Days cast members, including Kristian Alfonso, Roark Critchlow, Matthew Ashford, Kyle Lowder and Alison Sweeney, making crossover appearances.

From 1993 to 1998, actress Eileen Davidson portrayed multiple members of the same family, playing villainess Kristen DiMera as well as an entire doppelganger clan called the Banks family (four characters total, including one male), earning her first Daytime Emmy nomination in 1997.

Actor Matthew Ashford's character Jack Deveraux has been killed off and brought back from the dead multiple times, including a fourth death by an explosion-related elevator failure in August 2012, only to be revived again in December 2018; Ashford had earlier joked in 2006 about the storyline feeling like 'the Cartoon Network.'

In 2023, an investigation was launched against co-executive producer Albert Alarr following misconduct allegations from 30–40 individuals, mostly women; he was given a written warning initially, but was ultimately let go in August 2023 after cast members petitioned for his removal.

In February 2024, actress Arianne Zucker, known for playing Nicole Walker, filed a lawsuit against Corday Productions, Ken Corday, and Albert Alarr alleging sexual harassment and wrongful termination; a judge ruled in her favor in August 2024, and a settlement was filed in October 2025.