Scott had fought cancer since a diagnosis in late 2007, the cable TV sports network said, but remained dedicated to his craft even as he underwent chemotherapy, radiation and surgery.
ESPN President John Skipper said in a statement that Scott was "a true friend and a uniquely inspirational figure" and that his "energetic and unwavering devotion to his family and to his work while fighting the battle of his life left us in awe, and he leaves a void that can never be replaced."
On Sunday morning, NFL Network broadcaster Rich Eisen's voice broke as he reported the death of his good friend, with whom he worked on "SportsCenter" broadcasts.
Fans and players at games around the United States on Sunday stopped to observe moments of silence, including at NFL playoff games in Indianapolis and Arlington, Texas; the Mavericks-Cavaliers NBA game in Cleveland and at several college basketball games.
Some of the world's most famous athletes expressed their grief online. Basketball star LeBron James wrote on Instagram: "Thank you so much for being u and giving us inner city kids someone we could relate to that wasn't a player but was close enough to them."
"Stuart wasn't covering heroes & champions, it was the other way around," golfer Tiger Woods said on Twitter.
Born in Chicago, Scott attended high school in North Carolina. After graduating from the University of North Carolina in 1987, Scott worked at three TV stations in the southern U.S. before joining ESPN for the 1993 launch of its ESPN2 network, hosting short sports update segments.
He often anchored the 11 p.m. "SportsCenter," where he would punctuate emphatic highlights with "Boo-ya!"
Scott went on to cover countless major events for the network, including the Super Bowl, NBA finals, World Series and NCAA college basketball tournament. He also interviewed President Barack Obama, joining him for a televised game of one-on-one basketball.
"I will miss Stuart Scott," Obama said in a statement. "Stu helped usher in a new way to talk about our favourite teams and the day's best plays. For much of those 20 years, public service and campaigns have kept me from my family — but wherever I went, I could flip on the TV and Stu and his colleagues on 'SportsCenter' were there."
Scott was first diagnosed with cancer in November 2007 after he had to leave the "Monday Night Football" game between Miami and Pittsburgh to have his appendix removed. Doctors discovered a tumour during surgery. He underwent chemotherapy again in 2011.
Scott made a point of continuing to live his life — at work and outside of it.
"Who engages in mixed martial arts training in the midst of chemotherapy treatments?" Skipper said in ESPN's statement. "Who leaves a hospital procedure to return to the set?"
Scott accepted the Jimmy V Perseverance Award at the ESPYs, the ESPN sports award show, in July. The award is named for former North Carolina State University basketball coach Jim Valvano, who died of cancer in 1993.
During his speech, Scott noted: "When you die, that does not mean that you lose to cancer.
"You beat cancer by how you live, why you live, and the manner in which you live," Scott said. "So live. Live. Fight like hell."
AP Sports Writer Rachel Cohen contributed to this report.