Alexander graduated from Vassar College in 1945, majoring in anthropology. She fell into writing when she took a summer job as a copy clerk at the New York newspaper PM, where her mother worked. She worked as a freelance writer for Junior Bazaar and Mademoiselle magazines before becoming a researcher at Life for $65 a week in 1951. During the 1960s she wrote "The Feminine Eye" column for Life.

In 1962 she wrote an article for Life Magazine entitled “They Decide Who Lives, Who Dies: Medical miracle puts moral burden on small committee,” which sparked a national debate on the allocation of scarce dialysis machine resources.

Another Life magazine article, about a suicide hot line worker's efforts to keep a caller from killing herself, was turned into the 1965 film, The Slender Thread, which starred Sidney Poitier and Anne Bancroft.

In 1969 she became the first female editor at McCall's, but quit in 1971, complaining that it was a token job in a sexist environment. She was writing a column for Newsweek in 1975 when she replaced Nicholas von Hoffman on 60 Minutes, and debated Kilpatrick for the next four years. She played down this part of her career, commenting in 1979 that prior to that she "had been a writer, a columnist for Life magazine and for Newsweek -- that was about as high as you could get in column writing. I care about my writing. I'm not a quack-quack TV journalist." Still, the debates Alexander had with Kilpatrick were so prominent in American culture that they were famously satirized on Saturday Night Live, with Jane Curtin taking Alexander's role on "Weekend Update" opposite Dan Aykroyd's version of Kilpatrick ("Jane, you ignorant slut.")

She also wrote a number of nonfiction books, including Anyone's Daughter, a biography of kidnapped heiress Patricia Hearst. Her book Nutcracker, about Frances Schreuder, the convicted socialite who persuaded her son to kill her millionaire father, was made into a 1987 TV miniseries. Schreuder was played by actress Lee Remick.

Alexander had been married and divorced twice. Her only daughter, Kathy, committed suicide in 1987.

She had long been rumoured to have had an affair with the late Eugene McCarthy, but this was disputed by McCarthy's biographer, Dominic Sandbrook, in his 2005 book, Eugene McCarthy and The Rise and Fall of American Liberalism.

Shana Alexander died of cancer in Hermosa Beach, California, on June 23, 2005. She was 79 and had lived in Manhattan and Wainscott, New York, for many years. Reportedly, she had been in an assisted living facility. Alexander was survived by a sister, Laurel Bentley, and a niece.