Smith played college football for the Utah Utes, earning first-team All-American honors and winning the 2005 Fiesta Bowl as a senior.

He was traded to the Washington Redskins in 2018 to make way for Kansas City's second-year quarterback Patrick Mahomes, but was credited with helping develop the future NFL MVP.

[2][3][4] As a starter for the Helix Highlanders during his junior and senior years, Smith led his team to a record of 25–1, including two San Diego CIF section championships.

Smith was president of his senior class in high school, earned college credits through a program at San Diego State University, and took a dozen Advanced Placement tests.

Dealing with an injury and being taken in and out of the lineup by head coach Mike Nolan, Smith played in nine games in his rookie season, recording just one touchdown pass while throwing 11 interceptions.

Late in the quarter, with the same score, Smith struck again – shaking off an almost certain sack, rolling to the left and completing a pass to Frank Gore for a touchdown to give the 49ers a 10-point lead.

During the off-season, the 49ers added wide receivers Darrell Jackson, Ashley Lelie, and rookie Jason Hill as new offensive targets for Smith.

However, continuity in a poor system resulted in the team starting 0–5, and on September 27, Raye was fired and replaced by quarterbacks coach Mike Johnson.

[53] In Week 5, Smith was booed at home and the crowd chanted for his backup, David Carr, before leading the 49ers to two scoring drives to close within three points.

In a road game against the Philadelphia Eagles in Week 4, Smith rallied the team from a 23–3 second-half deficit to win 24–23, completing 9 of 9 passes for 179 yards and two touchdowns in the third quarter alone.

[69] Two weeks later, Smith led his third come-from-behind road victory of the year with a six-yard fourth and goal touchdown pass to tight end Delanie Walker, beating the Lions in Detroit 25–19.

[72] After 3 head coaches, 7 offensive coordinators, and 17 different starting wide receivers in the span of 7 seasons with the 49ers,[35] Smith would finally make his first playoff appearance.

[75][76] In this manner, The New York Times wrote that Smith was "a steady, if unspectacular, player surrounded by a solid team" in 2011, whose career year "underscored how much he struggled previously.

Shortly after Manning made the decision to join the Denver Broncos, Smith signed a three-year contract worth $24 million to remain with the 49ers.

[87] Harbaugh was impressed with Kaepernick, and said "we have two quarterbacks that have a hot hand" while dismissing any rule that a player should not lose their starting job due to an injury.

Smith was ranked third in the NFL in passer rating (104.1), led the league in completion percentage (70%), and had been 19–5–1 as a starter under Harbaugh, while Kaepernick was considered more dynamic with his scrambling ability and arm strength.

[90][91] Smith was medically cleared to play the day before the following game, but Harbaugh chose not to rush him back and again started Kaepernick, who threw and ran for a touchdown in a 31–21 win over the New Orleans Saints.

[100] The Chiefs were the last unbeaten team in the 2013 NFL season with Smith winning his first nine regular-season starts, gaining 1,919 passing yards with nine touchdowns compared to four interceptions.

[117] During the season opener, Smith finished with 368 passing yards and four touchdowns as the Chiefs pulled off a 42–27 road victory over the defending Super Bowl champion New England Patriots.

With a playoff spot already secured, Smith was given a rest in Week 17, and Chiefs' 2017 first round pick Patrick Mahomes made his NFL debut against the Denver Broncos.

[126] He was also credited as being instrumental in the development of Mahomes who would go on to be named NFL MVP in his first year as a starter and win multiple Super Bowls with the Chiefs.

[127][128] Rounding off his Chiefs career with two consecutive AFC West titles, Smith played a part in starting one of the longest eventual division-winning streaks in NFL history.

During a game against the Houston Texans on November 18, 2018, Smith suffered a spiral and compound fracture to his tibia and fibula in his right leg when he was sacked by Kareem Jackson and J. J.

[137][138] The injury drew parallels to former Washington quarterback Joe Theismann, who suffered a career-ending leg fracture in a game 33 years to the day prior in 1985.

[140] Doctors had suggested that an amputation above the knee might be his only option before performing skin grafts and an operation transferring muscle from his left quadriceps to save it.

He entered the game after Kyle Allen left with an arm injury and finished with nine completions for 37 yards while being sacked six times as Washington lost 30–10.

[150] Smith made his next appearance in Week 9 after Allen left the game with a dislocated ankle, where he threw for 325 yards with a touchdown and three interceptions in a 23–20 loss against the New York Giants.

[157][158][159] Smith returned for the regular-season finale against the Philadelphia Eagles, throwing for 162 yards, two touchdowns, and two interceptions in the 20–14 victory as Washington clinched the NFC East.

[160][161] However, he did not play in the 31–23 Wild Card Round loss against the eventual Super Bowl LV champion Tampa Bay Buccaneers due to lingering issues with his bone bruise.

[162][156][163] Following the season, Smith was named the NFL Comeback Player of the Year by the Associated Press,[164] Sporting News,[165] and Pro Football Writers of America (PFWA).