At Kansas, Simien received All-American honors his junior and senior years. He was a Wooden Award finalist both years, and was the Big 12 Player of the Year his senior year. However, his college career ended when Kansas was defeated by 14th-seeded Bucknell in the first round of the 2005 NCAA Tournament. Simien finished his college career with 110 wins and a 12-4 NCAA Tournament record.
He was selected with the 29th overall selection of the 2005 NBA Draft by the Miami Heat, with whom he won a championship in 2006.
Wayne married his wife, Katie, on July 8, 2006. Wayne could not participate in the Miami Heat's Summer League program because of a salmonella infection.