Zedd, Maren Morris and Grey took home the night's top honor at the annual award show at the Microsoft Theater in Los Angeles, winning Song of the Year for their collaborative track "The Middle"
Grande won two major prizes, including Artist of the Year and Pop Album of the Year.
"Thank you, it feels amazing. I am so honored," she said in a video tribute before a prerecorded performance of her new single "Needy."
Cardi B, who led the pack with 13 nominations, claimed the award for Hip Hop Artist of the Year and delivered a message to her "haters" in a video recording.
"Ya'll be sayin' means things and ya'll be thinking those mean things is gonna discourage me, but that just means we go harder," she said. "If everyone gives me compliments, I get comfortable."
Swift was one of several artists to take home special awards, winning the iHeartRadio Tour of the Year award for her Reputation stadium tour, which broke U.S. records, selling more than 2 million tickets.
"I've learned a lot -- life is really unpredictable. People can make forecasts and predictions, but they may not come true if there's an unforeseeable factor involved. And in this case, that factor was my fans. I honestly owe everything in my life to you," she said.
Swift also won the fan-voted award for Best Music Video for her song "Delicate" and teased new projects, saying "when there is new music, you will be the first to know."
Alicia Keys was honored with the iHeartRadio Innovator award for her contributions to pop culture and social causes as an artist, songwriter, producer, entrepreneur and activist.
"I'm finally more myself than I've ever been and even though it's a constant process, I encourage you to continue to find the power and the beauty and the unique story in your own journey," Keys said.
Halsey won the 2019 Fangirls award, recognizing "a female artist who has pushed boundaries with her music and message while inspiring her fans."
Garth Brooks was also presented with the first-ever iHeartRadio Artist of the Decade award.