The song gained national fame after being re-recorded by the white recording artist Pat Boone. Domino's version soon became more popular, bringing his music to the mass market a half-dozen years after his first recording, "The Fat Man".
After "Ain't That a Shame", mainstream artists began covering Domino's songs. Teresa Brewer, for instance, performed Domino's version of the folk song "Bo Weevil".
A version of the song by the Four Seasons reached number 22 on the Billboard charts in 1963.
According to legend, Pat Boone suggested changing the title and lyrics to "Isn't That a Shame" to make it more appealing to a broader audience but was dissuaded by his producers. Nevertheless, Boone's recording of the song in 1955 was his first Billboardnumber-one single. Domino complimented Boone's cover of the song. Boone liked to tell a story about a concert at which Domino invited Boone on stage, showed a big gold ring and said, "Pat Boone bought me this ring," since Domino and Bartholomew, as the song's writers, received royalties on it from record sales or radio airplay of other performers' cover versions of their song. 
Cheap Trick's version charted at #35 after being released on their live album Cheap Trick at Budokan. Reportedly, this was Fats Domino's favorite cover. Domino also gave Cheap Trick his gold record for his 1955 single, which is held by guitarist Rick Nielsen.