After first being diagnosed with cancer in November 2007 following an emergency appendectomy, Scott fought through three bouts of cancer, the network said.
“ESPN and everyone in the sports world have lost a true friend and a uniquely inspirational figure in Stuart Scott,” said ESPN president John Skipper in a statement.
During more than two decades with the network, Scott anchored ESPN's "SportsCenter," a sports news program, where he introduced such catchphrases as “boo-ya” and “as cool as the other side of the pillow.”
He also helped cover major sporting events such as the NBA Finals, the Super Bowl and the World Series and interviewed major sports figures, celebrities and politicians.
"I am deeply saddened because not only will not be replaced as a anchor or reporter but more than that as a genuine cool person," NBA superstar LeBron James said on Instagram.
Scott graduated from the University of North Carolina in 1987 with a bachelor of arts degree. He worked at television stations in North Carolina, South Carolina and Florida before joining ESPN in 1993.
Scott was diagnosed with cancer in November 2007 after an emergency appendectomy revealed a malignancy, according to ESPN. In 2011, Scott was diagnosed with cancer and entered remission in 2012. A year later, he was again diagnosed with cancer, the network said.
At the ESPYS, an awards show aired each year on ESPN, Scott in 2014 accepted the Jimmy V Award for Perseverance.
"When you die, it does not mean that you lose to cancer. You beat cancer by how you live, why you live, and in the manner in which you live," he said during his speech accepting the award named after college basketball coach Jimmy Valvano, who died of cancer in 1993.