Mathews attended California State University, Fresno from 2007 to 2010. As a freshman in 2007, Mathews rushed for 866 yards on 145 carries and scored 14 touchdowns. His rushing yard average and touchdowns led all NCAA freshman. Mathews was drafted by the San Diego Chargers with the 12th overall pick in the 2010 NFL draft. On August 1, 2010, Mathews signed a five-year, $26.65 million contract with the Chargers.