He played college football for the Missouri Tigers, and was selected by the San Francisco 49ers with the seventh overall pick in the 2011 NFL draft.

[11] Smith did not start but made his NFL debut in the season-opening 33–17 victory over the Seattle Seahawks, recording a pass deflection.

During a Week 15 20–3 victory over the Pittsburgh Steelers on Monday Night Football, Smith recorded four tackles and 2.5 sacks.

During the season-opening 30–22 road victory over the Green Bay Packers, Smith recorded four tackles and sacked Aaron Rodgers once.

[27] During a Week 15 41–34 road victory against the New England Patriots, Smith recorded a tackle, a pass deflection, and his first NFL interception off of Tom Brady.

[29][30] Smith finished his second professional season with 19.5 sacks, 66 tackles, three forced fumbles, an interception, and a pass deflection in 16 games and starts.

After a Week 3 27–7 loss to the Indianapolis Colts, Smith voluntarily entered a rehabilitation facility, to be put onto the non-football injury list with an indefinite leave of absence.

[41] Two weeks later against the Cleveland Browns, Smith got his first start of the year and finished the 27–20 road victory with two solo tackles and two pass deflections.

[42] In the next game against the Chicago Bears, he recorded a season-high six tackles and his first sack of the year as the Raiders narrowly lost on the road by a score of 22–20.

[43] Smith played his last game of the season in Week 10 against the Minnesota Vikings and finished the 30–14 loss with three tackles and a sack.

[44] Two days later, the NFL issued Smith a one-year suspension due to a hit-and-run incident that occurred on August 6, 2015.

[52][53] During the season-opening 20–17 road loss to the Los Angeles Rams on Sunday Night Football, Smith played in a regular season game for the first time since November 15, 2015.

During a Week 14 30–7 road victory over the Cincinnati Bengals, Smith recovered a fumble lost by running back Trayveon Williams and returned it 78 yards (fifth longest in franchise history) for his first NFL touchdown.

[65] On June 30, Smith was believed to have suffered stab wounds when attempting to break up a fight at a party at his Santa Clara County residence.

[66] On October 9, 2013, Smith was charged with "three felony counts of illegal possession of an assault weapon" relating to the stabbing incident.

After a Week 3 27–7 loss to the Indianapolis Colts, Smith voluntarily entered a rehabilitation facility, to be put onto the non-football injury list with an indefinite leave of absence.

[68] After interviews revealed that Smith did not clearly state he was carrying a bomb, the Los Angeles City Attorney decided to drop the charges.

On August 6, 2015, Smith was arrested in Santa Clara, California, for an alleged hit and run after driving under the influence, and vandalism charges.

[71][72] On September 23, 2017, it was announced that Smith had agreed to plead no contest to hit and run in the 2015 incident in exchange for the DUI charges being dropped.

[73] On March 3, 2018, a woman called the police from Smith's home and reported that he had consumed multiple bottles of tequila and then bit her wrists.

San Francisco police did not comment on the specifics, but did state that domestic violence of a "non-lethal" nature had occurred and they were seeking out Smith for questioning about the incident.

This picked up from the previous incident that occurred on March 3, where Smith pleaded not guilty on four misdemeanor counts, including: domestic violence, assault with force likely to produce great bodily injury, false imprisonment, and vandalism.

[75] On June 11, 2019, Smith was stopped by police in Mission, Kansas for a traffic violation, and later arrested on suspicion of driving under the influence.