He played college football for the Central Michigan Chippewas and was selected by the 49ers in the first round of the 2007 NFL draft.

During his high school career, he caught 24 passes for 559 yards, and earned seven touchdowns as a prep senior.

He also blocked for CMU's single-season total yardage record holder, Kent Smith.

Staley was invited to play in the 2007 East–West Shrine Game and he was named a preseason All-MAC First-team selection by Athlon Sports and MAC Report Online.

Staley was part of an offensive front that helped CMU boast a 1,000-yard rusher in three consecutive seasons.

He was a key part of an offensive line that allowed Kent Smith to pass for at least 2,000 yards in 2004 and 2005.

In the 2008 NFL season, Staley was moved to left tackle starting every game, allowing just 8.5 sacks.

On October 30, 2011, he caught a pass from a tackle eligible formation for a key first down in the 49ers' 20–10 victory over the Cleveland Browns.

[7] On December 27, 2011, Staley was named to the 2012 Pro Bowl and started at left tackle for the NFC.

In his final act as a 49er, Staley called the ceremonial coin toss on behalf of the captains of the 49ers and Chiefs, which included fellow CMU alumnus Eric Fisher who went on to accept the Vince Lombardi Trophy on behalf of the Chiefs' players.

On April 25, 2020, Staley announced his retirement from the NFL after 13 seasons, following the 49ers' acquisition of Trent Williams.