Kaepernick, whose protest against injustice and police brutality has been defended by U.S. President Barack Obama and since spread to other players and sports, will take over for a 49ers team that is 1-4 after losing four consecutive games.
"We're going to make a move at quarterback, and we're going to start Colin this week," 49ers head coach Chip Kelly told reporters. "It's a football decision."
By refusing to stand for "The Star-Spangled Banner" during the NFL's 2016 season, Kaepernick has made headlines and set off a national debate about race relations, policing and the mixing of politics and sports.
Many other athletes in the NFL and some in the National Basketball Association have since copied the gesture and the silent protests have angered some fans who call it disrespectful to the U.S. flag.
Kaepernick, drafted in the second round by San Francisco in 2011, burst upon the NFL midway through his second season in 2012 when he took over from an injured Alex Smith and led the 49ers to a berth in the Super Bowl.
He was once considered a franchise player and his ability to either throw or run the ball effectively led many to feel he could help redefine what it meant to be great at the position.
A stretch of poor play, however, cost Kaepernick his starting role.
While most backup NFL quarterbacks rarely make headlines, Kaepernick commanded the national spotlight starting in the preseason when he first chose to stay seated and then later opted to kneel during the playing of the anthem ahead of his team's games.
Since his protest began in August, Kaepernick's jersey has become a top-seller and fans at the 49ers' home stadium, have often chanted "We want Kaep" during games.
Kaepernick went 2-6 last season with a 59 percent completion rate, six touchdowns and five interceptions.
Sunday's game versus the host Buffalo Bills will mark Kaepernick's first start since last November.