In a post on social media, McCall said: "As you all know, I have battled injuries my whole career, but this is one I cannot come back from ... Brain specialists, my family and I have come to the conclusion that it is in my best interest to hang the cleats up."
McCall added that he would begin focusing on a coaching career.
In the most recent incident, McCall was taken off the field on a cart after being placed in a brace following a frightening first-quarter hit against Wake Forest on Oct. 5 that knocked his helmet off.
McCall ran for a gain of about 9 yards before he was hit by three Wake Forest defenders, Quincy Bryant, Dylan Hazen, and Nick Andersen. It appeared at least one Demon Deacon hit McCall with the crown of his helmet -- an infraction -- but the play was not reviewed and no flags were thrown, sparking outrage among the Wolfpack fan base.
The play caused McCall to fumble at the Wake Forest 10-yard line and the Deacs' Evan Slocum returned it 88 yards to the NC State 2-yard line.
McCall lay motionless on the field during the return. NC State medical personnel rushed onto the field as play continued.
NC State players immediately signaled for medical personnel after McCall was hit. Athletic trainers brought out a stretcher, cut off McCall's jersey and fitted him with a neck brace as Wolfpack players walked off the field in tears.
After a long delay, McCall was carried off the field. He held up two fingers to the crowd but otherwise kept his eyes covered as medical personnel brought him into the tunnel.
McCall was making his first start -- and ultimately his last -- after missing the previous two games because of an injury suffered against Louisiana Tech on Sept. 14.
After the game, coach Dave Doeren said McCall had passed all concussion protocols in advance of the Wake game and was cleared to play.
McCall has a history of concussions, including a serious head injury suffered the previous year while playing at Coastal Carolina that ended his season -- and nearly his career.
A native of Indian Trail, McCall was three times named Sun Belt Player of the Year at Coastal Carolina. He played at Porter Ridge High School before finding massive success at Coastal.
"This game has taken me places I never thought I would go, and has shaped my family and I in ways I never imagined," McCall wrote in his post. "I have made so many memories that will stay with me forever, and I am so grateful for that."
McCall threw for 10,005 yards and 88 touchdowns over 42 games for Coastal Carolina before transferring to NC State during the offseason. In four games for the Wolfpack, he passed for 518 yards and threw three touchdowns with two interceptions.
"As I feel like my whole world is being taken from me, I feel some sense of contentment," McCall said in his post. "Every time my feet hit the grass, I left every single ounce of myself on that field. I always played my hardest and to the best of my ability because I never knew what play would be my last. I have no regrets throughout my career and that is something I can be proud of."
True freshman CJ Bailey who started the previous two games, against Clemson and Northern Illinois, came on in relief of McCall. Bailey has since started in an Oct. 12 loss to Syracuse and a 24-23 win against Cal on Saturday, where he threw for more than 300 yards and two touchdowns.
NC State (4-4) has a bye this weekend.
ESPN and The Associated Press contributed