Following his college career, Smith was selected by the San Francisco 49ers with the first overall pick in the 2005 NFL Draft. During his first six seasons for them, he played for a different offensive coordinator each year, and struggled with injuries. Under head coach Jim Harbaugh in 2011 however, Smith enjoyed his strongest statistical season, leading the 49ers to their first NFC West division title and first playoff victory since 2002, along with their first NFC Championship Game appearance since 1997. The following season, Smith sustained a concussion in the middle of the season and was replaced by Colin Kaepernick. Despite posting strong statistical numbers during the season before the injury, Smith did not regain his starting position after he was medically cleared to play.