Henderson was born in 1917 in Tucson, Arizona, the daughter of Louis Rudolph Chlarson and Emily Vernell Rowley. She received a bachelor of arts in education from Arizona State College in 1940, and taught school in the Tucson area. She also taught in France, as well as to Japanese-American children in a Japanese relocation camp in Sacaton, Arizona, during World War II. She married Richard Harry Henderson in 1943, but they were divorced seven years later.

Henderson was one of the first female science fiction authors, and never used a male pen name. Although her work could not be considered feminist, Henderson was one of the few writers in the 1950s and 1960s writing science fiction from a female perspective. She began reading science fiction at age 12 from magazines such as Astounding Stories, Amazing Stories, and fantasy from Weird Tales.

The standard reference Contemporary Authors lists her religion as Methodist, though there is no known record of her being a member of any Methodist church. She was born and baptized into The Church of Jesus Christ of Latter-day Saints. But after her marriage, she was no longer a churchgoing Latter-day Saint, though she never renounced her membership. In an interview, she stated that she often included religious themes because her readers, particularly her young readers, liked them. She felt it was good to offer a word for "Our Sponsor" in her stories. In her later years, she attended an independent charismatic fellowship.

Zenna Henderson died of cancer in 1983 in Tucson, Arizona, and was buried in the St. David Cemetery, St. David, Arizona.

Most of her stories focus on the theme of being different, and often feature children or young people. Most are part of her series on the history of "The People", humanoid beings from a faraway planet who are forced to emigrate to (among other places) Earth when their home world is destroyed in a natural disaster. Scattered mostly throughout the American Southwest during their landing before 1900, they are set apart by their desire to preserve their home culture, including their religious and spiritual beliefs. Their unusual abilities ("Gifts") include telepathy, telekinesis, prophecy and healing, mostly manipulated through the "Signs and Persuasions". The stories describe groups of The People, as well as lonely isolated individuals, most often as they attempt to find communities and remain distinct in a world that does not understand them. This aspect of individuality was a common theme in most of Henderson's writing.

Beginning with Ararat (1952), Henderson's People stories appeared in magazines and anthologies, as well as the novelized Pilgrimage: The Book of the People (1961) and The People: No Different Flesh (1966). Other volumes include The People Collection (1991) and Ingathering: The Complete People Stories (1995).

Unlike the People stories, a more bitter, angry tone can be seen in stories collected in two volumes, The Anything Box and Holding Wonder, which in particular uses elementary teachers as narrators. She touches on mental illness in several tales, including obsessive-compulsive disorder in "Swept and Garnished", and agoraphobia in "Incident After". In "One Of Them", a woman's latent telepathic powers cause her to lose her identity as she unwittingly probes the minds of her co-workers. In "The Believing Child", a young daughter of a migrant worker believes so strongly in an imaginary magic word that its powers come true; she then uses her newfound powers to take revenge on her abusive classmates. And in "You Know What, Teacher?" a young girl confides in her teacher of her father's philandering, and of her mother's plan for revenge.

In the short story "The Closest School", a xenophobic school board president reaches outside himself to admit a gentle little girl who happens to be a furry, purple 14-eyed alien.

In 1971, Henderson's story "Pottage" was made into an ABC-TV Movie, The People, starring William Shatner, Kim Darby and Diane Varsi, and following the story of a group of humanoid extraterrestrials who live in an isolated rural community, disguised as a religious commune. It was the directorial debut for John Korty and was produced by his sometime partner Francis Ford Coppola.

She was nominated for a Hugo Award in 1959 for her novelette Captivity, and remains a favorite author of many science fiction fans worldwide, despite the fact that her books were long out of print until the 1995 release of Ingathering: The Complete People Stories of Zenna Henderson, published by the New England Science Fiction Association Press.