He played college football for the Ole Miss Rebels, earning consensus All-American honors in 2006 and was selected by the 49ers in the first round of the 2007 NFL draft.

Willis made the Pro Bowl in his first seven seasons and earned All-Pro honors in his first six years in the NFL.

Born in Bruceton, Tennessee, Willis grew up in abject poverty and had to take care of his younger siblings.

[1] At age 17, he left his home, a double-wide in a trailer park just outside Bruceton, with his brothers, Orey and Detris, and sister, Ernicka, when his alcoholic father turned increasingly violent.

Willis was selected by the San Francisco 49ers in the first round with the 11th overall pick in the 2007 NFL draft, re-uniting him with the staff that coached his South Squad at the 2007 Senior Bowl.

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.

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.

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 a game against the Arizona Cardinals on November 25, Willis ran down wide receiver Sean Morey after a 62-yard, catch-and-run for the game-saving tackle in overtime.

[16] Willis finished the 2007 campaign with an NFL-leading 174 total tackles, along with four sacks, two forced fumbles, and five passes deflected.

His season was capped by being named one of ESPN The Magazine's "NEXT" athletes of 2008, alongside Yankee Joba Chamberlain and Trail Blazer Brandon Roy.

[19] On December 16, during another dominating season with the 49ers, Willis was named the starting inside linebacker for the NFC Pro Bowl team.

[22] At the end of the year, Willis accumulated an NFL-leading 152 tackles along with four sacks, three forced fumbles, eight pass deflections and three interceptions.

He stayed in South Florida for the game and stood on the sideline in support of the NFC team and 49er teammates Frank Gore, Vernon Davis, Justin Smith and Andy Lee.

[24] Willis also became the second NFL player to win the Butkus Award since it was expanded in 2008 to include high school and professional winners in part to help end anabolic steroid abuse among young athletes.

[26] He now joins Hall of Fame safety Ronnie Lott as only 49ers to be selected to the Pro Bowl in each of their first four seasons.

Willis also earned first-team All-Pro from the Associated Press alongside Jerod Mayo of the New England Patriots.

"Nobody in the NFL plays their position better than Patrick Willis, and that is saying a lot," said Matt Williamson of Scouts Inc. "He is as good a linebacker as Peyton Manning is a quarterback, as Andre Johnson is a receiver, as Adrian Peterson is a running back.

"[30] Even 12-time Pro Bowler Ray Lewis, the dominant linebacker of his era, pointed to Willis as a worthy successor to his undisputed reign.

10 players of 2012 (2011 season), Ray Rice and commentators noted the resemblance in playing style and techniques from Willis to Lewis from 10 years ago[32] In 2011, Willis led a top ranked 49ers defense which set an NFL single season record of not allowing a rushing touchdown until week 16.

During a game against the St. Louis Rams in week 13, Willis landed awkwardly after missing a tackle and injured his right hamstring.

[35] Despite missing nearly four games due to the hamstring injury, Willis finished the season with 97 tackles along with two sacks, four forced fumbles, 12 pass deflections and an interception.

[38] During the 2012 season, Willis had 120 combined tackles, two forced fumbles (one recovery), two interceptions, nine passes defended, and 0.5 sacks.

Willis recorded ten combined tackles as the 49ers lost Super Bowl XLVII to the Baltimore Ravens by a score of 34–31.

On August 5, 2013, Willis underwent surgery to repair a fractured hand he suffered during training camp.

[47][48] His uncle, Arthur Willis, was a professional super middleweight boxer who later fought future world champion James Toney to a split decision.