Willis was coached directly by Hall of Fame middle-linebacker/coach Mike Singletary (who later became 49ers head coach), and eventually started at inside linebacker, specifically the "Mike" position, in the 49ers' 3-4 defense. In his first NFL game, Willis recorded 11 tackles, including 9 solo, and a forced fumble as the 49ers defeated the Arizona Cardinals in dramatic fashion by a score of 20–17. For his effort, he won the Diet Pepsi Rookie of the Week Award. One of Willis's strongest performances came against the Minnesota Vikings, as he led the 49ers defense in containing Offensive Rookie of the Year, Adrian Peterson, who managed just 3 yards on 14 carries. Willis's most impressive statistical performance came in week 16 at home against the Tampa Bay Buccaneers. In this game he recorded 20 total tackles, two sacks, one forced fumble and one pass deflected in a 21–19 victory, earning Rookie of the Week honors for the fourth time. In addition to receiving the award in weeks 1 and 16, Willis took home the award in weeks 2 and 12. He was also awarded the GMC Defensive Player of the Week twice.