Foursome Little Big Town picked up half of their six nominations, including their fourth win for Vocal Group of the Year.
Their hit song Girl Crush won top honours for Single of the Year and Song of the Year, a triumph the band was grateful for after the track sparked controversy earlier this year (15).
Some country music fans were angered by the track's supposed support of homosexuality, but the band members stood by the song.
"This is about being brave and being bold," singer Karen Fairchild declared upon accepting the Single of the Year award. "Country radio, thanks for having the guts to play it and for all the gatekeepers for not getting in the way of following our gut and our heart (sic), because the fans want to hear it. They want to hear it."
The night's other big winner was singer/songwriter Stapleton, who beat out the likes of Luke Bryan, Dierks Bentley and Eric Church for Male Vocalist of the Year, breaking fellow nominee Blake Shelton's five-year winning streak.
Stapleton was also named New Artist of the Year and his debut solo record, Traveller, won Album of the Year.
The former SteelDrivers frontman also provided one of the most memorable performances of the night, duetting with pop star Justin Timberlake. The singers covered Stapleton's breakout hit Tennessee Whiskey, and finished out the set with Timberlake's country-tinged track Drink You Away.
Luke Bryan was handed the top award of the night, Entertainer of the Year, and Miranda Lambert earned her sixth consecutive trophy for Female Vocalist of the Year, calling the prize a "needed a bright spot" this year. The singer split from husband Shelton in July (15).
Other winners included Florida Georgia Line (Vocal Duo of the Year) and duo Maddie & Tae, who took home the Music Video of the Year prize for Girl in a Country Song.
The evening at Nashville, Tennessee's Bridgestone Arena kicked off with two star-studded duets from Hank Williams, Jr. and Eric Church as well as John Mellencamp and Keith Urban, who sang the rocker's hit Pink Houses.
Co-hosts Carrie Underwood and Brad Paisley each took the stage to perform their latest singles, and there were also sets from Shelton, Lambert, Bryan, Little Big Town, Sam Hunt, Kacey Musgraves, Kenny Chesney, and Jason Aldean.
Thomas Rhett also collaborated with Fall Out Boy, and Reba MCEntire and Brooks & Dunn performed a medley of their classic songs.
Actors Kiefer Sutherland and Steve Martin, singer Edie Brickell, and a cappella group Pentatonix were among the presenters at the ceremony.
The full list of winners for the 2015 Country Music Association Awards is as follows:
Entertainer of the Year: Luke Bryan
Female Vocalist of the Year: Miranda Lambert
Male Vocalist of the Year: Chris Stapleton
Vocal Group of the Year: Little Big Town
Vocal Duo of the Year: Florida Georgia Line
New Artist of the Year: Chris Stapleton
Album of the Year: Traveller, Chris Stapleton
Song of the Year: Girl Crush, Little Big Town
Single of the Year: Girl Crush, Little Big Town
Music Video of the Year: Girl in a Country Song, Maddie & Tae
Musical Event of the Year: Raise 'Em Up, Keith Urban featuring Eric Church
Musician of the Year: MAC MCAnally.