“Ain’t It a Shame” was one of Fats Domino’s early crossover hits, and it was a top-selling record for both the R&B and pop music markets. The rise of R&B’s popularity led to many pop artists covering the songs of R&B musicians, often changing them in the process by altering tempos, removing horn sections, and adding minimizing regionalisms in vocal pronunciation to vocal pronunciation in order to appeal to a larger and more predominantly white audience.
The most successful cover of “Ain’t It a Shame,” renamed “Ain’t That a Shame,” was performed by Pat Boone, who made such alterations : singing without blues inflections on the melody, pronouncing lyrics without a regional accent, and replacing horns with backing vocals. Boone even suggested calling the song “Isn't That a Shame,” although he was overruled. Other artists from the era covered the song in different styles as well, including the Four Seasons, who added four-part harmonies, and Connie Francis, who performed the song in a country-western style.
In the decades after the song's initial success, artists such as John Lennon and Paul McCartney each made their own solo recordings of “Ain’t That a Shame,” and rock group Cheap Trick's version from Cheap Trick at Budokan made its way onto the Billboard charts almost twenty-five years after the initial release.