"Lake Marie" is arguably the album's most popular track. The song was inspired in part by Prine's crumbling marriage and a series of grisly murders the singer remembered the Chicago news media having a field day with when he was a kid. The John Prine Shrine website quotes the singer discussing his inspiration for the song: "It's an actual place along the Illinois-Wisconsin border. There's an entire chain of lakes along there, small lakes, and I remember as a teenager growing up in Chicago, a lot of the teenagers would go to these lakes and in the summer time kind of get away from the city. Lake Marie was kind of just one that stuck out in my mind. About '59, '60, '61, I grew up in Maywood - it's a western suburb of Chicago, and we started hearing about murders that weren't related to the mob. You know, John Wayne Gacy was like, about two towns away from me and you just hear about it. The suburbs were kind of thought to be a pretty safe place at the time, and then some of these unexplained murders would show up every once in a while, where they'd find people in the woods somewhere. I just kind of took any one of them, not one in particular, and put it as if it was in a TV newscast. It was a sharp left turn to take in a song, but when I got done with it, I kind of felt like it's what the song needed right then." In 2005 Lloyd Sachs wrote that the song was "one of Prine’s masterpieces." In a 2009 interview with The Huffington Post, Prine fan Bob Dylan commented, "If I had to pick one song of his, it might be 'Lake Marie.'"
"Quit Hollerin' At Me" reveals Prine's frustration with consumer culture and the need to escape from it while "Ain't Hurtin' Nobody" was inspired by one of the singer's childhood trips to the beach.
Lost Dogs and Mixed Blessings received favorable reviews upon release and was nominated for a Grammy award. Rolling Stone magazine commented, "Unlike virtually every other act in his age group, veteran singer/songwriter John Prine is doing the best work of his career right now." Writing for Allmusic, critic William Ruhlman wrote of the album "Fans of the early Prine may find that sound over-produced, but the songs never get lost, and with Prine's typically humorous, off-center view of the world..." Music critic Robert Christgau wrote "Prine's waggish pathos and lip-smacking Americanese have been whetted by the divorce that keeps nosing in where it's not wanted."