Dolphins Coach Cam Cameron said Brown tore the anterior cruciate ligament and will undergo surgery within the next seven to 10 days.
Cameron said Sunday's X-rays were negative, but a Monday MRI exam disclosed the damage.
Brown started the week leading the NFL in yards from scrimmage. He had 76 yards on 17 carries and caught five passes for 33 more before leaving Sunday's game. He had his streak of 100-yard rushing games stopped at four, one shy of Ricky Williams' club record.
In seven games this season, Brown has 602 yards rushing with a 5.1-yard average and four touchdowns. He also leads the team with 39 receptions for 389 yards with one score.
"You don't replace a Ronnie Brown," Cameron said Monday. "He was having a Pro Bowl season."