Keillor was born in Anoka, Minnesota, the son of Grace Ruth (née Denham) and John Philip Keillor, who was a carpenter and postal worker. He was raised in a family belonging to the Plymouth Brethren, a fundamentalist Christian denomination he has since left. He is six feet, three inches (1.9 m) tall and has Scottish ancestry. Keillor is a member of the Democratic-Farmer-Labor Party.[citation needed] In 2006 he told Christianity Today that he was attending an Episcopal church in Saint Paul, after previously attending a Lutheran church in New York. His religious roots are frequently worked into his material: he often remarks that most Minnesotans, being of German or Scandinavian descent, are Lutherans. He graduated from the University of Minnesota with a bachelor's degree in English in 1966. While there, he began his broadcasting career on the student-operated radio station known today as Radio K.

Keillor has been married three times:

Between his first and second marriages he was also romantically involved with Margaret Moos, who worked as a producer of A Prairie Home Companion.

The Keillors maintain homes on the Upper West Side of New York City and in Saint Paul, Minnesota.

One of his brothers, the historian Steven Keillor, is also an author.

On September 7, 2009, Keillor was briefly hospitalized after suffering a minor stroke.

Keillor has many noteworthy ancestors, including Joseph Crandall, who made progress in the studies of Native American languages and was also an associate of Roger Williams (who founded the first American Baptist church as well as Rhode Island), and Prudence Crandall (who founded the first African-American women's school in America).

Garrison Keillor started his professional radio career in November 1969 with Minnesota Educational Radio (MER), now Minnesota Public Radio (MPR) and distributing programs under the American Public Media (APM) brand. He hosted The Morning Program in the weekday drive time slot of 6 to 9 a.m. on KSJR 90.1 FM at St. John's University in Collegeville, which the station called "A Prairie Home Entertainment." The show's eclectic music was a major divergence from the station's usual classical music format. During this time he also began submitting fiction to The New Yorker, where his first story, "Local Family Keeps Son Happy," appeared on September 19, 1970.

Keillor resigned from The Morning Program in February 1971 to protest what he considered an attempt to interfere with his musical programming. The show became A Prairie Home Companion when he returned in October.

Keillor has attributed the idea for the live Saturday night radio program to his 1973 assignment to write about the Grand Ole Opry for The New Yorker, but he had already begun showcasing local musicians on the morning show, despite limited studio space for them, and in August 1973 The Minneapolis Tribune reported MER's plans for a Saturday night version of A Prairie Home Companion with live musicians.