Willis played college football for the University of Mississippi, and received All-American honors. The San Francisco 49ers chose him with the eleventh overall pick in the 2007 NFL Draft.

During Willis's senior season at Ole Miss, he received the Butkus Award and the Jack Lambert Award as the nation’s top linebacker. A year later as a member of the 49ers, Willis led the NFL in tackles, earned first-team All-Pro and Pro Bowl honors while being named the 2007 AP NFL Defensive Rookie of the Year.

He is the first player to receive the Butkus Award for best linebacker in more than one category. He won the college Butkus Award in 2006 while at Ole Miss and in 2009, he won the professional Butkus Award while with the San Francisco 49ers.

Willis is regarded by many as one of the best inside linebacker in the NFL.