The couple's first breakup moves came in 2012, eight years after their wedding, when Kimberly filed for divorce the first time.
"The marriage has become insupportable because of discord or conflict of personalities ... that destroys the legitimate ends of the marriage relationship and prevents any reasonable expectation of reconciliation," she said in court documents that year.
Dennis, now 62, followed up the Texas realtor's filing with his own petition later in 2012. But by 2013, their divorce filings had been dismissed, suggesting they'd resolved things -- until this week.
In a joint statement, the couple told TMZ their latest decision to split "was made amicably and with mutual respect toward one another."
Kimberly and Dennis are parents to a daughter and son, fraternal twins, Thomas and Zoe, whom they nearly lost after hospital workers gave them a nearly fatal dose of Heparin shortly after their birth. The twins are now 8.
"We will always remain great friends and devoted partners in raising our children," Dennis told the website.
In spite of the previous filings, the breakup comes as surprise for the Quaids, who earlier this year were seen vacationing together in Hawaii, where a photographer said they appeared to be "in high spirits."
The divorce marks the third ended marriage for Dennis, who's been in Vancouver, Canada, this week shooting "The Art of More." He was married to P.J. Soles until 1983 and to Meg Ryan until 2000.
While Meg Ryan's affair with Russell Crowe was the first infidelity in their marriage that went public, the actress later told InStyle, "It was a great story. But what wasn't in the story was the reality of my marriage for nine years. Dennis was not faithful to me for a long time, and that was very painful. I found out more about that once I was divorced... But Russell didn't break up the marriage. He was definitely there at the end, but it wasn't his fault."
Dennis later criticized Meg for revelations she made in the interview.
The two share a son, "Vinyl" actor Jack Henry, who's now 24.