The film features an ensemble cast including Woody Harrelson, Tommy Lee Jones, Garrison Keillor, Kevin Kline, Lindsay Lohan, Virginia Madsen, John C. Reilly, Maya Rudolph, Meryl Streep, and Lily Tomlin.

In Saint Paul, Minnesota, the long-running live radio variety show A Prairie Home Companion prepares for what the listening audience does not know is its final broadcast.

In between musical acts, and under the watchful eye of PI Guy Noir (Kevin Kline), the show's denizens mingle and reminisce, including: the singing Johnson Girls, Yolanda (Meryl Streep), her sister Rhonda (Lily Tomlin), and daughter Lola (Lindsay Lohan); cowboy duo Dusty (Woody Harrelson) and Lefty (John C. Reilly); pregnant PA Molly (Maya Rudolph); the Stage Manager, Makeup Lady, and Sound Effects Man (real life Radio Acting Co. members Tim Russell, Sue Scott, and Tom Keith); and the show's creator and host, Garrison Keillor (often called "GK").

A Prairie Home Companion opened the 2006 South by Southwest film festival on March 10, then premiered on May 3, 2006, at the Fitzgerald Theater, which had projection and sound equipment brought in for the purpose.

[10] Michael Medved (himself a radio host) gave the film one and a half stars out of four, saying, "The entertainment value stands somewhere between thin and nonexistent" and "[it may be] the worst movie ever made that pooled the talents of four (count ‘em – four!)

[11] Desson Thomson from The Washington Post fell in between, writing in a review headlined "Honey, You Could Ask for More" (a reference to the radio show's theme song) that while the movie had its strengths, it was weaker than it should have been.