Lederer was a profile-raiser for several medical charities, and in 1977 President Carter appointed her to a six-year term on a cancer advisory board.
Born in Sioux City, Iowa, Esther Pauline and her identical twin sister Pauline Esther ("Popo", who was 17 minutes younger) were daughters of Russian Jewish immigrants Rebecca Friedman (née Rushall) and Abraham B. Friedman. They grew up in Sioux City and attended its Morningside College for three and a half years (1936–39), where they wrote a gossip column for the college's newspaper. Eppie majored in journalism and psychology.
During Lederer's career writing the Ann Landers column, her sister wrote a similar personal advice column, Dear Abby, under the name Abigail Van Buren, which she initiated in San Francisco a few months after Eppie took over as Ann Landers in Chicago. As competing columnists they had a discordant relationship. They reconciled publicly in 1964, but acrimony between them persisted. In her July 8, 2017 Dear Abby column, Jeanne Phillips said her mother liked being a twin while her aunt wanted to be an individual, and this also caused conflict between them. Just a few years before Eppie's death, they were not on speaking terms.
In her later years, Lederer wrote her column at home, sometimes while in the bathtub. She had numerous friends and was a regular part of the Chicago social scene.
In July 1939, at the age of 21, Eppie and Popo were married in a double-wedding ceremony on July 2, 1939, 2 days before their joint birthday. There were 750 guests, and hundreds more who stood outside to watch. Eppie was married to Jules Lederer, who became a business executive; Popo married Morton Phillips of Minneapolis.
For many years, the Lederers lived in Chicago, where they owned a large, well-furnished apartment. Lederer often said that she exercised regularly by walking the length of her apartment several times a day.
In March 1940, she gave birth to her only child, Margo, who became an advice columnist herself almost 60 years later, as Margo Howard. In 1944, at the age of 56, Lederer's mother Rebecca Friedman died of a cerebral hemorrhage. Jules had been conscripted for the war; she and Margo had been living with the Friedmans.
Between 1945 and 1949, Lederer was chairwoman of the Minnesota-Wisconsin council of the Anti Defamation League.
Ruth Crowley, the creator of the Chicago Sun-Times' Ask Ann Landers column, died in 1955. During her nine years writing the column, intermittently from 1943, Crowley's identity had been kept secret. Lederer won a contest to take over the column later that year, and took on the identity. Long before the end of her 47 years as Ann Landers, she had become a North American media celebrity, having appeared on television and traveled the continent to media and charity events. In her later years, Lederer began answering questions about homosexuality and other topics that had once been taboo in print. In a 1993 interview, she said she was happy for the dissolution of restrictions she had to work under in the 1950s.
She appeared on the March 18, 1956 episode of What's My Line?.
From the early 1970s until her death, Lederer lived at 209 East Lake Shore Drive, in a 14-room, high-rise apartment.
Jules and Eppie divorced in 1975. In her column of July 1, 1975, Lederer wrote, "The sad, incredible fact is, that after 36 years of marriage, Jules and I are being divorced." She received 30,000 sympathetic letters in response.
Lederer was in good health almost all her life. She was diagnosed with multiple myeloma in January 2002 and died on June 22, having refused any medical treatment for her condition. Her former husband had died on January 21, 1999.
After Lederer's death, her longtime editors Kathy Mitchell and Marcy Sugar started writing the Annie's Mailbox column. Lederer's desk was purchased by Dan Savage, author of the relationship-and-sex advice column Savage Love.
In 2002, the Chicago City Council passed a two-page resolution to honor Lederer for epitomizing Chicago "with her strong opinion, her sage advice, her impeccable manners, and quick wit", and announced that a street sign, "Ann 'Eppie' Landers Way", would be installed at the corner of North Michigan Avenue and East Illinois Street, in front of the Chicago Tribune Tower, the headquarters of her home paper since 1987. The nicknaming of the street was celebrated with a parade and sparklers—a favorite of hers.
In 2003, a collection of correspondence between Lederer and her daughter was published.
In 2006, David Rambo wrote a play about the life and work of Lederer as Ann Landers,. The production was revived in 2008 at the Pasadena Playhouse in California, starring Mimi Kennedy.