He played college football for the Oklahoma State Cowboys, and was selected by the Arizona Cardinals in the fifth round of the 2004 NFL draft.

Smith helped the Cardinals reach Super Bowl XLIII, but the team would lose 27–23 to the Pittsburgh Steelers.

In 2011, Smith went to his first career Pro Bowl, replacing the New England Patriots' Andre Carter who was unable to play due to injury.

[5] In 2013, Smith was suspended for week one after an incident in the preseason in which he removed Miami Dolphins lineman Richie Incognito's helmet and swung it at him.

[6] On November 29, 2013, he was fined $15,750 for hitting Jacksonville Jaguars' quarterback Chad Henne in the head and neck region.

[13] Antonio Smith shares his knowledge and talent by volunteering his time as a defensive line coach for the Christian Heritage high school football team (Del City, OK).