The actress, 52, and the rocker, 62, split recently after dating for more than three years, PEOPLE has confirmed.
"It was the distance," a source tells PEOPLE. "She lives in New York and he resides in Indiana. It was the long distance that ultimately was the cause."
The pair – who were last spotted together in May – became an item in late 2010, shortly after Mellencamp's split from wife Elaine after 18 years of marriage.
They kept a low profile during the past three years, stepping out together for the occasional industry event and being spotted now and again on the streets of New York.
But Indiana native Mellencamp had expressed his unhappiness at calling New York City home.
"I'm too sensitive to live there," he told Rolling Stone in December. "I can't see poor people. I can't see the suffering. I can't see the trash on the streets." When it comes to paparazzi attention, he added, "I don't like it for [Ryan]. "I'm not leaving Indiana. I'm going to die here."
Both stars have big projects coming up: Mellencamp, a father of five, is poised to release his 22nd album, Plain Spoken, in November. Meanwhile, Ryan, who has son Jack, 22, with ex-husband Dennis Quaid, and daughter Daisy, 9, has been busy working on her directorial debut, Ithaca, a WWII coming-of-age drama that's being executive-produced by Ryan's Sleepless in Seattle costar Tom Hanks.
The film marks a major return to Hollywood for the very private actress, who has deliberately avoided the spotlight since making her last major film, 2008's The Women. The onetime soap star had been poised to make her small-screen return this fall with a new pilot and the role of the narrator in the planned How I Met Your Mother spin-off, but neither show was picked up.
Reps for the pair have not yet commented. Closer Weekly first broke news of the split.
Reporting by MARY MARGARET